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Kwon KW, Choi E, Kim H, Kim HW, Choi S, Lee S, Ha SJ, Shin SJ. Adjunctive beneficial effect of c-di-GMP, a STING agonist, in enhancing protective efficacy of TLR4-adjuvanted tuberculosis subunit vaccine formulations. J Biomed Sci 2025; 32:52. [PMID: 40414893 DOI: 10.1186/s12929-025-01144-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 05/06/2025] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND Effective subunit vaccine development requires selecting appropriate adjuvant formulations to trigger desired adaptive immune responses. This study explores the immunogenicity and tuberculosis (TB) vaccine potential of antigens (Ags) combined with Toll-like receptor 4 (TLR4) adjuvants and a stimulator of interferon genes (STING) agonist. METHODS In this work, we investigated the combination of Ags with TLR4 adjuvants (monophosphoryl lipid A / dimethyldioctadecylammonium bromide; MPL/DDA or glucopyranosyl lipid adjuvant-stable emulsion; GLA-SE) and a STING agonist, c-di-GMP (CDG). Mice were immunized three times by intramuscular injections at 3-week intervals. The effects of integrating Ags in these adjuvant formulations on the immune response were evaluated, focusing on the generation of Th1-biased, polyfunctional Ag-specific CD4+ T cells and their localization in the lung and spleen. To assess protection, immunized mice were aerogenically challenged with either conventional or ultra-low doses of Mycobacterium tuberculosis (Mtb) 4 weeks after the last immunization. Subsequently, bacterial load and pulmonary inflammation were assessed. RESULTS Integrating ESAT6 Ag in TLR4 and CDG adjuvant formulations remarkably boosted Th1-biased, polyfunctional ESAT6-specific CD4+ T cells in the lungs and spleen, providing durable protection against Mtb infection. The inclusion of CDG promoted mucosal localization of ESAT6-specific CD4+ T cells resembling resident memory phenotypes in the lung parenchyma and increased Ag-specific CD4+ T cells in lung vasculature. Immunization with another vaccine Ag candidate, Ag85B, in GLA-SE plus CDG similarly increased Ag85B-specific CD4+ T cells in the spleen and both lung compartments. Following ultra-low dose Mtb challenge, ESAT6 or Ag85B/GLA-SE/CDG immunizations significantly reduced bacterial loads compared to non-, Bacillus Calmette-Guérin (BCG)-, and ESAT6 or Ag85B/GLA-SE-immunized groups. Importantly, the inclusion of CDG decreased killer cell lectin-like receptor subfamily G member 1 (KLRG1) expression among Ag-specific CD4+ T cells in the lung, correlating with enhanced lung-homing evidenced by expanded lung parenchyma Ag-specific CD4+ T cells, including less-differentiated Th1 cells. CONCLUSIONS This study highlights that CDG, when used in combination with TLR4 adjuvants, enhances long-term protective immunity, offering a promising strategy for subunit TB vaccine development.
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Affiliation(s)
- Kee Woong Kwon
- Department of Microbiology and Convergence of Medical Science, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
- Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Eunsol Choi
- Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Hagyu Kim
- Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Hyeong Woo Kim
- Department of Microbiology and Convergence of Medical Science, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Sangwon Choi
- Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Seunghyun Lee
- Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Sang-Jun Ha
- Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, 03722, South Korea
- Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, 03722, Republic of Korea
| | - Sung Jae Shin
- Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, South Korea.
- Institute for Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, 03722, South Korea.
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Xie M, Tsai CY, Woo J, Nuritdinov F, Cristaldo M, Odjourian NM, Antilus-Sainte R, Dougher M, Gengenbacher M. BAFF and APRIL immunotherapy following Bacille Calmette-Guérin vaccination enhances protection against pulmonary tuberculosis in mice. Front Immunol 2025; 16:1551183. [PMID: 39981256 PMCID: PMC11839638 DOI: 10.3389/fimmu.2025.1551183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 01/21/2025] [Indexed: 02/22/2025] Open
Abstract
Introduction Bacille Calmette-Guérin (BCG), the only tuberculosis vaccine currently in clinical use, provides inadequate long-term protection. Administered at birth, BCG induces broad immune responses against a large number of antigens shared with Mycobacterium tuberculosis (Mtb), but protection wanes over time. We have previously shown that unconventional B cell subsets play a role in tuberculosis control. Methods High-dimensional flow cytometry and multiplex cytokine analysis were employed to investigate the effects of immunotherapy on BCG-vaccinated mice in an Mtb challenge model. Results In this study, we investigate the potential of recombinant cytokines targeting B cells - B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) - to modulate BCG immunity and improve protection in mice. Both cytokines play overlapping roles in B cell development and peripheral survival. Following subcutaneous BCG vaccination, immunotherapy with BAFF or APRIL resulted in an increased frequency of unconventional B cells potentially transitioning into antibody-producing plasma cells. Concurrently, we observed an increased frequency of central memory T cells, a subset critical for protective immunity. Changes in cellular immune responses were accompanied by reduced pro-inflammatory cytokine profiles and a contraction of the leukocyte population in lungs. Importantly, mice receiving BCG vaccination followed by BAFF or APRIL immunotherapy exhibited superior long-term protection against pulmonary tuberculosis relative to controls that received only BCG. Conclusion In summary, our findings demonstrate that combining BCG vaccination with B cell targeted immunomodulatory therapies can improve long-term protection against pulmonary tuberculosis, highlighting the continued relevance and underutilized potential of BCG as a vaccine platform.
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Affiliation(s)
- Min Xie
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Chen-Yu Tsai
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Joshua Woo
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Frank Nuritdinov
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Melissa Cristaldo
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Narineh M. Odjourian
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | | | - Maureen Dougher
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Martin Gengenbacher
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
- Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, United States
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Lan C, Qiu M, Lin M. Zinc Finger Proteins in Colorectal Cancer: Insights into Molecular Mechanisms and Therapeutic Implications. Technol Cancer Res Treat 2025; 24:15330338251334447. [PMID: 40208082 PMCID: PMC12032436 DOI: 10.1177/15330338251334447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025] Open
Abstract
Colorectal cancer ranks as one of the most common malignancies globally, with mortality rates second only to lung cancer. Despite improvements in diagnostic and therapeutic approaches, long-term survival rates for colorectal cancer patients remain unsatisfactory. The onset and progression of this disease involve intricate molecular mechanisms, influenced by a range of biological factors. Zinc finger proteins play a critical role in these processes, impacting tumor development and patient prognosis. This review summarizes current research on zinc finger proteins in colorectal cancer, highlighting key findings and advancements in understanding their role in tumor biology.
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Affiliation(s)
- Chongyuan Lan
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ming Qiu
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Minglin Lin
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
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Solaymani-Mohammadi S. The IL-21/IL-21R signaling axis regulates CD4+ T-cell responsiveness to IL-12 to promote bacterial-induced colitis. J Leukoc Biol 2024; 116:726-737. [PMID: 38498592 PMCID: PMC11408709 DOI: 10.1093/jleuko/qiae069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/21/2024] [Accepted: 03/06/2024] [Indexed: 03/20/2024] Open
Abstract
IL-21/IL-21R signaling dysregulation is linked to multiple chronic intestinal inflammatory disorders in humans and animal models of human diseases. In addition to its critical requirement for the generation and development of germinal center B cells, IL-21/IL-21R signaling can also regulate the effector functions of a variety of T-cell subsets. The antibody-mediated abrogation of IL-21/IL-21R signaling led to the impaired expression of IFN-γ by mucosal CD4+ T cells from human subjects with colitis, suggesting an IL-21/IL-21R-triggered positive feedback loop of the TH1 immune response in the colon. Despite recent advances in our understanding of the mechanisms underpinning the regulation of proinflammatory immune responses by the IL-21/IL-21R signaling axis, it remains unclear how this pathway or its downstream molecules contribute to inflammation during bacterial-induced colitis. This study found that IL-21 enhances the surface expression of IL-12Rβ2, but not IL-12Rβ1, in CD4+ T cells, leading to TH1 differentiation and stability. Consistently, these findings also point to an indispensable role of the IL-12Rβ2 signaling axis in promoting proinflammatory immune responses during Citrobacter rodentium-induced colitis. Genetic deletion of the IL-12Rβ2 signaling pathway led to the attenuation of C. rodentium-induced colitis in vivo. The genetic deletion of the IL-12Rβ2 signaling pathway did not alter the host's ability to respond adequately to C. rodentium infection or the ability of Il12rb2-/- mice to express antigen-specific cytokines (IFN-γ, IL-17A). IL-21 is a pleiotropic cytokine exerting a wide range of immunomodulatory functions in multiple tissues, and its direct targeting may result in undesirable off-target consequences. These findings highlight the possibility for targeted manipulations of signaling cascades downstream of main regulators of proinflammatory responses to control invading pathogens while preserving the integrity of host immune responses. A better understanding of the novel mechanisms by which IL-21/IL-21R signaling regulates bacterial-induced colitis will provide insights into the development of new therapeutic and preventive strategies to harness IL-21/IL-21R signaling or its downstream molecules to treat infectious colitis.
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Affiliation(s)
- Shahram Solaymani-Mohammadi
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 North Columbia Road, Suite W315, Stop 9037, Grand Forks, ND, United States
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Xiang X, Zhang J, Yue Y. Pyroptosis: A major trigger of excessive immune response in the gingiva. Oral Dis 2024; 30:4152-4160. [PMID: 38852159 DOI: 10.1111/odi.15013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/21/2024] [Accepted: 05/17/2024] [Indexed: 06/11/2024]
Abstract
OBJECTIVES The gingival mucosal barrier, an important oral cavity barrier, plays a significant role in preventing pathogenic microorganism invasion and maintaining periodontal tissue health. Pathogenic microorganism invasion of the gingival mucosa produces a large number of cytokines. Among them, pyroptosis is an important player in exacerbating immune-inflammatory responses, leading to tissue destruction. However, the mechanism of pyroptosis and the immune response it triggers have not been fully elucidated. We provide an overview of recent advances in understanding gingival physical barrier pyroptosis and inflammation-induced hyperimmunity. METHODS PubMed, Web of Science databases were searched for articles, reviews, and clinical studies published until March 2024. RESULTS We summarised the importance of the gingival barrier in terms of the functions of different cells, described the progress in research on gingival epithelial cell and gingival fibroblast pyroptosis and the immune-inflammatory response it induces, and discussed the relationship between pyroptosis and systemic diseases, association of multiple cell death systems. Finally, we propose future directions for pyroptosis research. CONCLUSIONS Pyroptosis often triggers a range of inflammatory immune responses that lead to associated diseases. Therefore, further study of the molecular mechanisms of pyroptosis and the immune responses is warranted.
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Affiliation(s)
- Xueyu Xiang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jing Zhang
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yuan Yue
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Singer M, Husseiny MI. Immunological Considerations for the Development of an Effective Herpes Vaccine. Microorganisms 2024; 12:1846. [PMID: 39338520 PMCID: PMC11434158 DOI: 10.3390/microorganisms12091846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/27/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
Research is underway to develop a vaccine to prevent and cure infection from herpes simplex virus (HSV). It emphasizes the critical need for immunization to address public health issues and the shortcomings of existing treatment options. Furthermore, studies on the HSV vaccine advance the field of immunology and vaccine creation, which may help in the battle against other viral illnesses. The current lack of such a vaccine is, in part, due to herpes viral latency in sensory ganglions. Current vaccines rely on tissue-resident memory CD8+ T cells, which are known to provide protection against subsequent HSV reinfection and reactivation without correlating with other immune subsets. For that reason, there is no effective vaccine that can provide protection against latent or recurrent herpes infection. This review focuses on conventional methods for evaluating the efficacy of a herpes vaccine using differential CD8+ T cells and important unaccounted immune aspects for designing an effective vaccine against herpes.
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Affiliation(s)
- Mahmoud Singer
- School of Medicine, University of California Irvine, Irvine, CA 92617, USA
| | - Mohamed I. Husseiny
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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7
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Ahmed R, Feldman AL. CD8-positive T-cell lymphoproliferative disorder of the uterus: a new subtype of indolent extranodal T-cell neoplasm? J Hematop 2024; 17:179-182. [PMID: 38977645 DOI: 10.1007/s12308-024-00589-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/29/2024] [Indexed: 07/10/2024] Open
Abstract
A 51-year-old female with menorrhagia was found to have a cervical polyp. Polypectomy and endometrial curettage showed an atypical lymphoid infiltrate. Hysterectomy was performed, showing extensive myometrial infiltration by small, cytologically bland CD3-positive αβ T cells with a non-activated cytotoxic phenotype and a low proliferative rate. PCR showed clonal TCR-β gene rearrangement. Lymph nodes were uninvolved. PET-CT was negative. A diagnosis of CD8-positive T-cell lymphoproliferative disorder (T-LPD) was made. At 6 months, the patient was asymptomatic with a negative repeat PET-CT. A critical recent advance in the classification of lymphoid neoplasms is the recognition of indolent extranodal T-LPDs, including those of the gastrointestinal tract (T-cell and NK-cell types) and skin (small/medium CD4-positive and acral CD8-positive). However, T-LPDs of the uterus are rare. Two indolent T-LPDs of the uterus have been reported, both showing a CD8-positive, nonactivated cytotoxic phenotype, low proliferative rate, and clonal TCR rearrangement. Neither developed systemic disease nor recurrence. The etiology of indolent T-LPDs and their relationship to overt T-cell lymphomas remain poorly understood. T-LPDs of the uterus may arise from effector memory T-cells that establish long-term, tissueresident immunologic memory following exposure to fetal extravillous trophoblastic cell alloantigens during a previous pregnancy. Neither our patient nor the 2 previously reported had a current pregnancy or a known recent infection or toxic exposure, and the event(s) triggering evolution into T-LPD are unknown. Indolent T-LPDs can be encountered at new and unusual extranodal sites; knowledge of their clinicopathological features will help avoid unnecessary cytotoxic chemotherapy and improve understanding of this group of disorders.
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Affiliation(s)
- Reham Ahmed
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
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Girard A, Vimonpatranon S, Chan A, Jiang A, Huang DW, Virtaneva K, Kanakabandi K, Martens C, Goes LR, Soares MA, Licavoli I, McMurry J, Doan P, Wertz S, Wei D, Ryk DV, Ganesan S, Hwang IY, Kehrl JH, Martinelli E, Arthos J, Cicala C. MAdCAM-1 co-stimulation combined with retinoic acid and TGF-β induces blood CD8 + T cells to adopt a gut CD101 + T RM phenotype. Mucosal Immunol 2024; 17:700-712. [PMID: 38729611 PMCID: PMC11323166 DOI: 10.1016/j.mucimm.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/12/2024] [Accepted: 04/30/2024] [Indexed: 05/12/2024]
Abstract
Resident memory T cells (TRMs) help control local immune homeostasis and contribute to tissue-protective immune responses. The local cues that guide their differentiation and localization are poorly defined. We demonstrate that mucosal vascular addressin cell adhesion molecule 1, a ligand for the gut-homing receptor α4β7 integrin, in the presence of retinoic acid and transforming growth factor-β (TGF-β) provides a co-stimulatory signal that induces blood cluster of differentiation (CD8+ T cells to adopt a TRM-like phenotype. These cells express CD103 (integrin αE) and CD69, the two major TRM cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and α4β7, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for αEβ7. Fluorescent lifetime imaging indicated an αEβ7 and E-cadherin cis interaction on the plasma membrane. This report advances our understanding of the signals that drive the differentiation of CD8+ T cells into resident memory T cells and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue-specific immunotherapies.
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Affiliation(s)
- Alexandre Girard
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Sinmanus Vimonpatranon
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA; Department of Retrovirology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
| | - Amanda Chan
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Andrew Jiang
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Da Wei Huang
- NCI, Lymphoid Malignancy Branch, Bethesda, Maryland, USA
| | - Kimmo Virtaneva
- National Institute of Allergy and Infectious Diseases, Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, Hamilton, Montana, USA
| | - Kishore Kanakabandi
- National Institute of Allergy and Infectious Diseases, Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, Hamilton, Montana, USA
| | - Craig Martens
- National Institute of Allergy and Infectious Diseases, Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, Hamilton, Montana, USA
| | - Livia R Goes
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA; INCA, Rio de Janeiro, Brazil
| | | | - Isabella Licavoli
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Jordan McMurry
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Pearl Doan
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Samuel Wertz
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Danlan Wei
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Donald Van Ryk
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Sundar Ganesan
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Il Young Hwang
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - John H Kehrl
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Elena Martinelli
- Northwestern Feinberg School of Medicine, Division of Infectious Diseases, Chicago, Illinois, USA
| | - James Arthos
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA
| | - Claudia Cicala
- National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, Bethesda, Maryland, USA.
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Boggiatto PM, Sterle H, Falkenberg S, Sarlo-Davila K, Putz EJ, Olsen SC. Characterization of the adaptive cellular and humoral immune responses to persistent colonization of Brucella abortus strain RB51 in a Jersey cow. Front Vet Sci 2024; 11:1367498. [PMID: 39132440 PMCID: PMC11312097 DOI: 10.3389/fvets.2024.1367498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 07/15/2024] [Indexed: 08/13/2024] Open
Abstract
Brucella abortus strain RB51 is the commercial cattle vaccine used in the United States (US) and many parts of the world against bovine brucellosis. RB51 was licensed for use in 1996, and it has been shown to be safe and efficacious in cattle, eliciting humoral and cellular responses in calves and adult animals. In 2017, an epidemiological trace-back investigation performed by the Centers for Disease Control and Prevention (CDC) identified human cases of brucellosis caused by infection with RB51. These infections resulted from the consumption of unpasteurized dairy products, which were traced back to otherwise healthy animals that were shedding RB51 in their milk. At the current time, six adult Jersey cows have been identified in the U.S. that are shedding RB51 in milk. One of the RB51 shedding cattle was obtained and housed at the National Animal Disease Center (NADC) for further study. Improved understanding of host cellular and humoral immune responses to RB51 in persistently colonized cattle may be achieved by the characterization of responses in shedding animals. We hypothesized, based on the lack of RB51 clearance, that the RB51 shedder animal has a diminished adaptive cellular immune response to RB51. Our data demonstrate that in the presence of persistent RB51 infection, there is a lack of peripheral anti-RB51 CD4+ T cell responses and a concurrently high anti-RB51 IgG humoral response. By understanding the mechanisms that result in RB51 persistence, the development of improved interventions or vaccinations for brucellosis may be facilitated, which would provide public health benefits, including reducing the risks associated with the consumption of non-pasteurized milk products.
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Affiliation(s)
- Paola M. Boggiatto
- Infectious Bacterial Diseases Research Unit, National Animal Disease Center, Ames, IA, United States
| | - Haley Sterle
- Infectious Bacterial Diseases Research Unit, National Animal Disease Center, Ames, IA, United States
- Immunobiology Interdepartmental Program, Iowa State University, Ames, IA, United States
| | - Shollie Falkenberg
- Auburn University College of Veterinary Medicine, Auburn, AL, United States
| | - Kaitlyn Sarlo-Davila
- Ruminant Diseases and Immunology Unit, National Animal Disease Center, Ames, IA, United States
| | - Ellie J. Putz
- Infectious Bacterial Diseases Research Unit, National Animal Disease Center, Ames, IA, United States
| | - Steven C. Olsen
- Infectious Bacterial Diseases Research Unit, National Animal Disease Center, Ames, IA, United States
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10
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Xiong H, Shen Z. Tissue-resident memory T cells in immunotherapy and immune-related adverse events by immune checkpoint inhibitor. Int J Cancer 2024; 155:193-202. [PMID: 38554117 DOI: 10.1002/ijc.34940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/05/2024] [Accepted: 03/07/2024] [Indexed: 04/01/2024]
Abstract
Tissue-resident memory T cells (TRM) are a specialized subset of T cells that reside in tissues and provide long-term protective immunity against pathogens that enter the body through that specific tissue. TRM cells have specific phenotype and reside preferentially in barrier tissues. Recent studies have revealed that TRM cells are the main target of immune checkpoint inhibitor immunotherapy since their role in cancer immunosurveillance. Furthermore, TRM cells also play a crucial part in pathogenesis of immune-related adverse events (irAEs). Here, we provide a concise review of biological characteristics of TRM cells, and the major advances and recent findings regarding their involvement in immune checkpoint inhibitor immunotherapy and the corresponding irAEs.
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Affiliation(s)
- Hao Xiong
- Department of Dermatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhu Shen
- Department of Dermatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
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11
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Rodger B, Stagg AJ, Lindsay JO. The role of circulating T cells with a tissue resident phenotype (ex-T RM) in health and disease. Front Immunol 2024; 15:1415914. [PMID: 38817613 PMCID: PMC11137204 DOI: 10.3389/fimmu.2024.1415914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 04/26/2024] [Indexed: 06/01/2024] Open
Abstract
Tissue-resident memory T cells (TRM) are long-lived memory lymphocytes that persist in non-lymphoid tissues and provide the first line of defence against invading pathogens. They adapt to their environment in a tissue-specific manner, exerting effective pathogen control through a diverse T cell receptor (TCR) repertoire and the expression of proinflammatory cytokines and cytolytic proteins. More recently, several studies have indicated that TRM can egress from the tissue into the blood as so-called "ex-TRM", or "circulating cells with a TRM phenotype". The numerically small ex-TRM population can re-differentiate in the circulation, giving rise to new memory and effector T cells. Following their egress, ex-TRM in the blood and secondary lymphoid organs can be identified based on their continued expression of the residency marker CD103, alongside other TRM-like features. Currently, it is unclear whether exit is a stochastic process, or is actively triggered in response to unknown factors. Also, it is not known whether a subset or all TRM are able to egress. Ex-TRM may be beneficial in health, as mobilisation of specialised TRM and their recruitment to both their site of origin as well as distant tissues results in an efficient distribution of the immune response. However, there is emerging evidence of a pathogenic role for ex-TRM, with a suggestion that they may perpetuate both local and distant tissue inflammation. Here, we review the evidence for the existence of ex-TRM and examine their potential involvement in disease pathogenesis.
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Affiliation(s)
- Beverley Rodger
- Blizard Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Andrew J. Stagg
- Blizard Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - James O. Lindsay
- Blizard Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
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12
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Elliott Williams M, Hardnett FP, Sheth AN, Wein AN, Li ZRT, Radzio-Basu J, Dinh C, Haddad LB, Collins EMB, Ofotokun I, Antia R, Scharer CD, Garcia-Lerma JG, Kohlmeier JE, Swaims-Kohlmeier A. The menstrual cycle regulates migratory CD4 T-cell surveillance in the female reproductive tract via CCR5 signaling. Mucosal Immunol 2024; 17:41-53. [PMID: 37866719 PMCID: PMC10990418 DOI: 10.1016/j.mucimm.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 10/24/2023]
Abstract
Despite their importance for immunity against sexually transmitted infections, the composition of female reproductive tract (FRT) memory T-cell populations in response to changes within the local tissue environment under the regulation of the menstrual cycle remains poorly defined. Here, we show that in humans and pig-tailed macaques, the cycle determines distinct clusters of differentiation 4 T-cell surveillance behaviors by subsets corresponding to migratory memory (TMM) and resident memory T cells. TMM displays tissue-itinerant trafficking characteristics, restricted distribution within the FRT microenvironment, and distinct effector responses to infection. Gene pathway analysis by RNA sequencing identified TMM-specific enrichment of genes involved in hormonal regulation and inflammatory responses. FRT T-cell subset fluctuations were discovered that synchronized to cycle-driven CCR5 signaling. Notably, oral administration of a CCR5 antagonist drug blocked TMM trafficking. Taken together, this study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of immune surveillance at the site of STI pathogen exposure.
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Affiliation(s)
- M Elliott Williams
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Felica P Hardnett
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Anandi N Sheth
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine and Grady Health System, Atlanta, GA, USA
| | - Alexander N Wein
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Zheng-Rong Tiger Li
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jessica Radzio-Basu
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Chuong Dinh
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Lisa B Haddad
- Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Elizabeth M B Collins
- Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Igho Ofotokun
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine and Grady Health System, Atlanta, GA, USA
| | - Rustom Antia
- Department of Biology, Emory University, Atlanta, GA, USA
| | - Christopher D Scharer
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - J Gerardo Garcia-Lerma
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Jacob E Kohlmeier
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Alison Swaims-Kohlmeier
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA; Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA; Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA, USA.
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13
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Park SI, Park S, Lee K, Kwak HW, Kim YK, Park HJ, Bang YJ, Kim JY, Kim D, Seo KW, Lee SJ, Kim H, Kim Y, Kim DH, Park HJ, Jung SY, Ga E, Hwang J, Na W, Hong SH, Lee SM, Nam JH. Intranasal immunization with the recombinant measles virus encoding the spike protein of SARS-CoV-2 confers protective immunity against COVID-19 in hamsters. Vaccine 2024; 42:69-74. [PMID: 38097457 DOI: 10.1016/j.vaccine.2023.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 10/12/2023] [Accepted: 12/02/2023] [Indexed: 01/01/2024]
Abstract
BACKGROUND As the nasal mucosa is the initial site of infection for COVID-19, intranasal vaccines are more favorable than conventional vaccines. In recent clinical studies, intranasal immunization has been shown to generate higher neutralizing antibodies; however, there is a lack of evidence on sterilizing immunity in the upper airway. Previously, we developed a recombinant measles virus encoding the spike protein of SARS-CoV-2 (rMeV-S), eliciting humoral and cellular immune responses against SARS-CoV-2. OBJECTIVES In this study, we aim to provide an experiment on nasal vaccines focusing on a measles virus platform as well as injection routes. STUDY DESIGN Recombinant measles viruses expressing rMeV-S were prepared, and 5 × 105 PFUs of rMeV-S were administered to Syrian golden hamsters via intramuscular or intranasal injection. Subsequently, the hamsters were challenged with inoculations of 1 × 105 PFUs of SARS-CoV-2 and euthanized 4 days post-infection. Neutralizing antibodies and RBD-specific IgG in the serum and RBD-specific IgA in the bronchoalveolar lavage fluid (BALF) were measured, and SARS-CoV-2 clearance capacity was determined via quantitative reverse-transcription PCR (qRT-PCR) analysis and viral titer measurement in the upper respiratory tract and lungs. Immunohistochemistry and histopathological examinations of lung samples from experimental hamsters were conducted. RESULTS The intranasal immunization of rMeV-S elicits protective immune responses and alleviates virus-induced pathophysiology, such as body weight reduction and lung weight increase in hamsters. Furthermore, lung immunohistochemistry demonstrated that intranasal rMeV-S immunization induces effective SARS-CoV-2 clearance that correlates with viral RNA content, as determined by qRT-PCR, in the lung and nasal wash samples, SARS-CoV-2 viral titers in lung, nasal wash, BALF samples, serum RBD-specific IgG concentration, and RBD-specific IgA concentration in the BALF. CONCLUSION An intranasal vaccine based on the measles virus platform is a promising strategy owing to the typical route of infection of the virus, the ease of administration of the vaccine, and the strong immune response it elicits.
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Affiliation(s)
| | - Sohyun Park
- Chungbuk National University, Cheongju, Republic of Korea
| | - Kunse Lee
- SK Bioscience, Seongnam, Republic of Korea
| | - Hye Won Kwak
- SML Biopharm, Gwangmyeong, Republic of Korea; The Catholic University of Korea, Bucheon, Republic of Korea
| | | | - Hyeong-Jun Park
- SML Biopharm, Gwangmyeong, Republic of Korea; The Catholic University of Korea, Bucheon, Republic of Korea
| | - Yoo-Jin Bang
- The Catholic University of Korea, Bucheon, Republic of Korea
| | - Jae-Yong Kim
- The Catholic University of Korea, Bucheon, Republic of Korea
| | - Daegeun Kim
- SML Biopharm, Gwangmyeong, Republic of Korea
| | | | | | - Hun Kim
- SK Bioscience, Seongnam, Republic of Korea
| | - Yeonhwa Kim
- Chungbuk National University, Cheongju, Republic of Korea
| | - Do-Hyung Kim
- SML Biopharm, Gwangmyeong, Republic of Korea; The Catholic University of Korea, Bucheon, Republic of Korea
| | - Hyo-Jung Park
- The Catholic University of Korea, Bucheon, Republic of Korea
| | | | - Eulhae Ga
- Chonnam National University, Gwangju, Republic of Korea
| | - Jaehyun Hwang
- Chonnam National University, Gwangju, Republic of Korea
| | - Woonsung Na
- Chonnam National University, Gwangju, Republic of Korea
| | - So-Hee Hong
- Ewha Womans University, Seoul, Republic of Korea
| | | | - Jae-Hwan Nam
- The Catholic University of Korea, Bucheon, Republic of Korea.
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14
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Kobayashi O, Taguchi A, Nakajima T, Ikeda Y, Saito K, Kawana K. Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer. Taiwan J Obstet Gynecol 2024; 63:22-28. [PMID: 38216264 DOI: 10.1016/j.tjog.2023.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 01/14/2024] Open
Abstract
Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.
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Affiliation(s)
- Osamu Kobayashi
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Takahiro Nakajima
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Keisuke Saito
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan.
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15
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Zhang Z, Duan Z, Cui Y. CD8 + T cells in brain injury and neurodegeneration. Front Cell Neurosci 2023; 17:1281763. [PMID: 38077952 PMCID: PMC10702747 DOI: 10.3389/fncel.2023.1281763] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/30/2023] [Indexed: 02/19/2024] Open
Abstract
The interaction between the peripheral immune system and the brain is increasingly being recognized as an important layer of neuroimmune regulation and plays vital roles in brain homeostasis as well as neurological disorders. As an important population of T-cell lymphocytes, the roles of CD8+ T cells in infectious diseases and tumor immunity have been well established. Recently, increasing number of complex functions of CD8+ T cells in brain disorders have been revealed. However, an advanced summary and discussion of the functions and mechanisms of CD8+ T cells in brain injury and neurodegeneration are still lacking. Here, we described the differentiation and function of CD8+ T cells, reviewed the involvement of CD8+ T cells in the regulation of brain injury including stroke and traumatic brain injury and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and discussed therapeutic prospects and future study goals. Understanding these processes will promote the investigation of T-cell immunity in brain disorders and provide new intervention strategies for the treatment of brain injury and neurodegeneration.
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Affiliation(s)
- Zhaolong Zhang
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zhongying Duan
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, Shandong, China
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Cui
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, Shandong, China
- Qingdao Medical College, Qingdao University, Qingdao, China
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16
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Wu Q, Pan C, Zhou Y, Wang S, Xie L, Zhou W, Ding L, Chen T, Qian J, Su R, Gao X, Mei Z, Qiao Y, Yin S, Wu Y, Wang J, Zhou L, Zheng S. Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment. Hepatology 2023; 78:1402-1417. [PMID: 36811396 DOI: 10.1097/hep.0000000000000320] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 01/09/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND AIMS Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. APPROACH RESULTS Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4 + Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4 + Tregs to CD8 + T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1 + 4-1BB - Tregs stepwise develop to the Nrp-1 - 4-1BB + Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. CONCLUSION Our findings elucidate the potential mechanism of anti-PD-1-mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.
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Affiliation(s)
- Qinchuan Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Caixu Pan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Yuan Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shuai Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, China
| | - Liting Xie
- Department of Ultrasound, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wuhua Zhou
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Limin Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Tianchi Chen
- Department of vascular surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Rong Su
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Xingxing Gao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Zhibin Mei
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Shengyong Yin
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Yi Wu
- Lyvgen Biopharma, Shanghai, China
| | | | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, China
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17
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Rathore APS, St John AL. Promises and challenges of mucosal COVID-19 vaccines. Vaccine 2023; 41:4042-4049. [PMID: 37045682 PMCID: PMC10083204 DOI: 10.1016/j.vaccine.2023.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/29/2023] [Accepted: 04/04/2023] [Indexed: 04/14/2023]
Abstract
Coronavirus disease-2019 (COVID-19) is an ongoing pandemic caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, COVID-19 vaccines are given intramuscularly and they have been shown to evoke systemic immune responses that are highly efficacious towards preventing severe disease and death. However, vaccine-induced immunity wanes within a short time, and booster doses are currently recommended. Furthermore, current vaccine formulations do not adequately restrict virus infection at the mucosal sites, such as in the nasopharyngeal tract and, therefore, have limited capacity to block virus transmission. With these challenges in mind, several mucosal vaccines are currently being developed with the aim of inducing long-lasting protective immune responses at the mucosal sites where SARS-COV-2 infection begins. Past successes in mucosal vaccinations underscore the potential of these developmental stage SARS-CoV-2 vaccines to reduce disease burden, if not eliminate it altogether. Here, we discuss immune responses that are triggered at the mucosal sites and recent advances in our understanding of mucosal responses induced by SARS-CoV-2 infection and current COVID-19 vaccines. We also highlight several mucosal SARS-COV-2 vaccine formulations that are currently being developed or tested for human use and discuss potential challenges to mucosal vaccination.
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Affiliation(s)
- Abhay P S Rathore
- Department of Pathology, Duke University Medical Center, Durham, North Carolina 27705, USA
| | - Ashley L St John
- Department of Pathology, Duke University Medical Center, Durham, North Carolina 27705, USA; Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, 169857 Singapore, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; SingHealth Duke-NUS Global Health Institute, Singapore.
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18
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Montero DA, Vidal RM, Velasco J, George S, Lucero Y, Gómez LA, Carreño LJ, García-Betancourt R, O’Ryan M. Vibrio cholerae, classification, pathogenesis, immune response, and trends in vaccine development. Front Med (Lausanne) 2023; 10:1155751. [PMID: 37215733 PMCID: PMC10196187 DOI: 10.3389/fmed.2023.1155751] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/14/2023] [Indexed: 05/24/2023] Open
Abstract
Vibrio cholerae is the causative agent of cholera, a highly contagious diarrheal disease affecting millions worldwide each year. Cholera is a major public health problem, primarily in countries with poor sanitary conditions and regions affected by natural disasters, where access to safe drinking water is limited. In this narrative review, we aim to summarize the current understanding of the evolution of virulence and pathogenesis of V. cholerae as well as provide an overview of the immune response against this pathogen. We highlight that V. cholerae has a remarkable ability to adapt and evolve, which is a global concern because it increases the risk of cholera outbreaks and the spread of the disease to new regions, making its control even more challenging. Furthermore, we show that this pathogen expresses several virulence factors enabling it to efficiently colonize the human intestine and cause cholera. A cumulative body of work also shows that V. cholerae infection triggers an inflammatory response that influences the development of immune memory against cholera. Lastly, we reviewed the status of licensed cholera vaccines, those undergoing clinical evaluation, and recent progress in developing next-generation vaccines. This review offers a comprehensive view of V. cholerae and identifies knowledge gaps that must be addressed to develop more effective cholera vaccines.
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Affiliation(s)
- David A. Montero
- Departamento de Microbiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Roberto M. Vidal
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Instituto Milenio de Inmunología e Inmunoterapia, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Juliana Velasco
- Unidad de Paciente Crítico, Clínica Hospital del Profesor, Santiago, Chile
- Programa de Formación de Especialista en Medicina de Urgencia, Universidad Andrés Bello, Santiago, Chile
| | - Sergio George
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Yalda Lucero
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Pediatría y Cirugía Infantil, Hospital Dr. Roberto del Rio, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Leonardo A. Gómez
- Departamento de Microbiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Leandro J. Carreño
- Instituto Milenio de Inmunología e Inmunoterapia, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Richard García-Betancourt
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Miguel O’Ryan
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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19
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Qiu Z, Khairallah C, Chu TH, Imperato JN, Lei X, Romanov G, Atakilit A, Puddington L, Sheridan BS. Retinoic acid signaling during priming licenses intestinal CD103+ CD8 TRM cell differentiation. J Exp Med 2023; 220:e20210923. [PMID: 36809399 PMCID: PMC9960115 DOI: 10.1084/jem.20210923] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 12/02/2022] [Accepted: 02/01/2023] [Indexed: 02/23/2023] Open
Abstract
CD8 tissue-resident memory T (TRM) cells provide frontline protection at barrier tissues; however, mechanisms regulating TRM cell development are not completely understood. Priming dictates the migration of effector T cells to the tissue, while factors in the tissue induce in situ TRM cell differentiation. Whether priming also regulates in situ TRM cell differentiation uncoupled from migration is unclear. Here, we demonstrate that T cell priming in the mesenteric lymph nodes (MLN) regulates CD103+ TRM cell differentiation in the intestine. In contrast, T cells primed in the spleen were impaired in the ability to differentiate into CD103+ TRM cells after entry into the intestine. MLN priming initiated a CD103+ TRM cell gene signature and licensed rapid CD103+ TRM cell differentiation in response to factors in the intestine. Licensing was regulated by retinoic acid signaling and primarily driven by factors other than CCR9 expression and CCR9-mediated gut homing. Thus, the MLN is specialized to promote intestinal CD103+ CD8 TRM cell development by licensing in situ differentiation.
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Affiliation(s)
- Zhijuan Qiu
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Camille Khairallah
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Timothy H. Chu
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Jessica N. Imperato
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Xinyuan Lei
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Galina Romanov
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Amha Atakilit
- Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Lynn Puddington
- Department of Immunology, University of Connecticut Health, Farmington, CT, USA
| | - Brian S. Sheridan
- Department of Microbiology and Immunology, Center for Infectious Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
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20
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Kitakaze M, Uemura M, Hara T, Chijimatsu R, Motooka D, Hirai T, Konno M, Okuzaki D, Sekido Y, Hata T, Ogino T, Takahashi H, Miyoshi N, Ofusa K, Mizushima T, Eguchi H, Doki Y, Ishii H. Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer. Br J Cancer 2023; 128:1828-1837. [PMID: 36869093 PMCID: PMC10147592 DOI: 10.1038/s41416-023-02202-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 01/30/2023] [Accepted: 02/06/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Tissue-resident memory T (Trm) cells are associated with cytotoxicity not only in viral infection and autoimmune disease pathologies but also in many cancers. Tumour-infiltrating CD103+ Trm cells predominantly comprise CD8 T cells that express cytotoxic activation and immune checkpoint molecules called exhausted markers. This study aimed to investigate the role of Trm in colorectal cancer (CRC) and characterise the cancer-specific Trm. METHODS Immunochemical staining with anti-CD8 and anti-CD103 antibodies for resected CRC tissues was used to identify the tumour-infiltrating Trm cells. The Kaplan-Meier estimator was used to evaluate the prognostic significance. Cells immune to CRC were targeted for single-cell RNA-seq analysis to characterise cancer-specific Trm cells in CRC. RESULTS The number of CD103+/CD8+ tumour-infiltrating lymphocytes (TILs) was a favourable prognostic and predictive factor of the overall survival and recurrence-free survival in patients with CRC. Single-cell RNA-seq analysis of 17,257 CRC-infiltrating immune cells revealed a more increased zinc finger protein 683 (ZNF683) expression in cancer Trm cells than in noncancer Trm cells and in high-infiltrating Trm cells than low-infiltrating Trm in cancer, with an upregulated T-cell receptor (TCR)- and interferon-γ (IFN-γ) signalling-related gene expression in ZNF683+ Trm cells. CONCLUSIONS The number of CD103+/CD8+ TILs is a prognostic predictive factor in CRC. In addition, we identified the ZNF683 expression as one of the candidate markers of cancer-specific Trm cells. IFN-γ and TCR signalling and ZNF683 expression are involved in Trm cell activation in tumours and are promising targets for cancer immunity regulation.
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Affiliation(s)
- Masatoshi Kitakaze
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Tomoaki Hara
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Ryota Chijimatsu
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Daisuke Motooka
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Toshiro Hirai
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Masamitsu Konno
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.,National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, 135-0064, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Yuki Sekido
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Tsuyoshi Hata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Ken Ofusa
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.,Prophoenix Division, Food and Life-Science Laboratory, Idea Consultants, Inc., Osaka-city, Osaka, 559-8519, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Hideshi Ishii
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
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21
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Anand A, Singh R, Saini S, Mahapatra B, Singh A, Singh S, Singh RK. Leishmania donovani induces CD300a expression to dampen effector properties of CD11c + dendritic and antigen activated CD8 + T cells. Acta Trop 2023; 239:106826. [PMID: 36610528 DOI: 10.1016/j.actatropica.2023.106826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/11/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023]
Abstract
CD8+ T cells are an important regiment of adaptive immunity that play a decisive role in elimination of many species of Leishmania parasite from the host. In visceral leishmaniasis, caused by L. donovani, the loss of CD8+ T cells function has been found associated with augmented pathogenesis. The factors determining CD8+ T cells activation and function against Leishmania antigens are largely unknown. In this study, we investigated the role of an immune inhibitory receptor, CD300a, on the effector properties of dendritic cells and CD8+ T cells. We observed that the Leishmania regulates the effectors function of CD8+ T cells by increasing CD300a expression on CD11c+ dendritic cells. The abrogation of CD300a signaling in parasites infected animals induced CD8+ T cell abilities to produce IFN-γ, TNF-α and also helped them to acquire desired multifunctionality. The CD300a receptor blocking also enhanced the number of CD8+ T cells memory phenotypes at the early days of infection, suggesting its potential beneficial role in vaccine induced immunity. We also observed significantly enhanced levels of pro-inflammatory cytokines in the spleen of CD300a blocked infected animals with concomitant reduced spleen parasite load. Additionally, the abrogation of CD300a signals in the infected animals helped in establishing Th1 type protective humoral immunity with significantly elevated levels of IgG2a antibodies. Since CD8+ T cells are an important determinant of vaccine induced immunity against leishmaniasis, the findings corroborate the potential of CD300a in vaccine induced immunity and thus require further attention.
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Affiliation(s)
- Anshul Anand
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Rajan Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Shashi Saini
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Baishakhi Mahapatra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Abhishek Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Samer Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Science, Banaras Hindu University, Varanasi 221005, India
| | - Rakesh K Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
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22
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Vimonpatranon S, Goes LR, Chan A, Licavoli I, McMurry J, Wertz SR, Arakelyan A, Huang D, Jiang A, Huang C, Zhou J, Yolitz J, Girard A, Van Ryk D, Wei D, Hwang IY, Martens C, Kanakabandi K, Virtaneva K, Ricklefs S, Darwitz BP, Soares MA, Pattanapanyasat K, Fauci AS, Arthos J, Cicala C. MAdCAM-1 costimulation in the presence of retinoic acid and TGF-β promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells. PLoS Pathog 2023; 19:e1011209. [PMID: 36897929 PMCID: PMC10032498 DOI: 10.1371/journal.ppat.1011209] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/22/2023] [Accepted: 02/15/2023] [Indexed: 03/11/2023] Open
Abstract
CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-β, promote the differentiation of CD4+ T cells into a distinct subset α4β7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis.
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Affiliation(s)
- Sinmanus Vimonpatranon
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Center of Excellence for Microparticle and Exosome in Diseases, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Livia R Goes
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
- Oncovirology Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Amanda Chan
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Isabella Licavoli
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Jordan McMurry
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Samuel R Wertz
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Anush Arakelyan
- Eunice Kennedy-Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, United States of America
- Georgiamune, Gaithersburg, Maryland, United States of America
| | - Dawei Huang
- Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Andrew Jiang
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Cindy Huang
- Bioinformatics Program, St. Bonaventure University, St. Bonaventure, New York, United States of America
| | - Joyce Zhou
- Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Jason Yolitz
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Alexandre Girard
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Donald Van Ryk
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Danlan Wei
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Il Young Hwang
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Craig Martens
- Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, National Institutes of Allergy and Infectious Diseases, Hamilton, Montana, United States of America
| | - Kishore Kanakabandi
- Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, National Institutes of Allergy and Infectious Diseases, Hamilton, Montana, United States of America
| | - Kimmo Virtaneva
- Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, National Institutes of Allergy and Infectious Diseases, Hamilton, Montana, United States of America
| | - Stacy Ricklefs
- Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, National Institutes of Allergy and Infectious Diseases, Hamilton, Montana, United States of America
| | - Benjamin P Darwitz
- Research Technologies Section, Genomics Unit, Rocky Mountain Laboratory, National Institutes of Allergy and Infectious Diseases, Hamilton, Montana, United States of America
| | - Marcelo A Soares
- Oncovirology Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
- Department of Genetics, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Kovit Pattanapanyasat
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Center of Excellence for Microparticle and Exosome in Diseases, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Anthony S Fauci
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - James Arthos
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Claudia Cicala
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
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23
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von Werdt D, Gungor B, Barreto de Albuquerque J, Gruber T, Zysset D, Kwong Chung CKC, Corrêa-Ferreira A, Berchtold R, Page N, Schenk M, Kehrl JH, Merkler D, Imhof BA, Stein JV, Abe J, Turchinovich G, Finke D, Hayday AC, Corazza N, Mueller C. Regulator of G-protein signaling 1 critically supports CD8 + T RM cell-mediated intestinal immunity. Front Immunol 2023; 14:1085895. [PMID: 37153600 PMCID: PMC10158727 DOI: 10.3389/fimmu.2023.1085895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/13/2023] [Indexed: 05/09/2023] Open
Abstract
Members of the Regulator of G-protein signaling (Rgs) family regulate the extent and timing of G protein signaling by increasing the GTPase activity of Gα protein subunits. The Rgs family member Rgs1 is one of the most up-regulated genes in tissue-resident memory (TRM) T cells when compared to their circulating T cell counterparts. Functionally, Rgs1 preferentially deactivates Gαq, and Gαi protein subunits and can therefore also attenuate chemokine receptor-mediated immune cell trafficking. The impact of Rgs1 expression on tissue-resident T cell generation, their maintenance, and the immunosurveillance of barrier tissues, however, is only incompletely understood. Here we report that Rgs1 expression is readily induced in naïve OT-I T cells in vivo following intestinal infection with Listeria monocytogenes-OVA. In bone marrow chimeras, Rgs1 -/- and Rgs1 +/+ T cells were generally present in comparable frequencies in distinct T cell subsets of the intestinal mucosa, mesenteric lymph nodes, and spleen. After intestinal infection with Listeria monocytogenes-OVA, however, OT-I Rgs1 +/+ T cells outnumbered the co-transferred OT-I Rgs1- /- T cells in the small intestinal mucosa already early after infection. The underrepresentation of the OT-I Rgs1 -/- T cells persisted to become even more pronounced during the memory phase (d30 post-infection). Remarkably, upon intestinal reinfection, mice with intestinal OT-I Rgs1 +/+ TRM cells were able to prevent the systemic dissemination of the pathogen more efficiently than those with OT-I Rgs1 -/- TRM cells. While the underlying mechanisms are not fully elucidated yet, these data thus identify Rgs1 as a critical regulator for the generation and maintenance of tissue-resident CD8+ T cells as a prerequisite for efficient local immunosurveillance in barrier tissues in case of reinfections with potential pathogens.
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Affiliation(s)
- Diego von Werdt
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Bilgi Gungor
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | | | - Thomas Gruber
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Daniel Zysset
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Cheong K. C. Kwong Chung
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- Department of Gastrointestinal Health, Immunology, Nestlé Research, Lausanne, Switzerland
| | - Antonia Corrêa-Ferreira
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Regina Berchtold
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Nicolas Page
- Department of Pathology, Division of Clinical Pathology, University & University Hospitals of Geneva, Geneva, Switzerland
| | - Mirjam Schenk
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - John H. Kehrl
- National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States
| | - Doron Merkler
- Department of Pathology, Division of Clinical Pathology, University & University Hospitals of Geneva, Geneva, Switzerland
| | - Beat A. Imhof
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- Department of Pathology and Immunology, Centre Medical Universitaire, University of Geneva, Geneva, Switzerland
| | - Jens V. Stein
- Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland
| | - Jun Abe
- Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland
| | - Gleb Turchinovich
- Department of Biomedicine, and University Children’s Hospital Basel, University of Basel, Basel, Switzerland
| | - Daniela Finke
- Department of Biomedicine, and University Children’s Hospital Basel, University of Basel, Basel, Switzerland
| | - Adrian C. Hayday
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Nadia Corazza
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- *Correspondence: Christoph Mueller, ; Nadia Corazza,
| | - Christoph Mueller
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- Department of Biomedicine, and University Children’s Hospital Basel, University of Basel, Basel, Switzerland
- *Correspondence: Christoph Mueller, ; Nadia Corazza,
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24
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Lobby JL, Uddbäck I, Scharer CD, Mi T, Boss JM, Thomsen AR, Christensen JP, Kohlmeier JE. Persistent Antigen Harbored by Alveolar Macrophages Enhances the Maintenance of Lung-Resident Memory CD8 + T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1778-1787. [PMID: 36162870 PMCID: PMC9588742 DOI: 10.4049/jimmunol.2200082] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 08/16/2022] [Indexed: 11/07/2022]
Abstract
Lung tissue-resident memory T cells are crucial mediators of cellular immunity against respiratory viruses; however, their gradual decline hinders the development of T cell-based vaccines against respiratory pathogens. Recently, studies using adenovirus (Ad)-based vaccine vectors have shown that the number of protective lung-resident CD8+ TRMs can be maintained long term. In this article, we show that immunization of mice with a replication-deficient Ad serotype 5 expressing influenza (A/Puerto Rico/8/34) nucleoprotein (AdNP) generates a long-lived lung TRM pool that is transcriptionally indistinct from those generated during a primary influenza infection. In addition, we demonstrate that CD4+ T cells contribute to the long-term maintenance of AdNP-induced CD8+ TRMs. Using a lineage tracing approach, we identify alveolar macrophages as a cell source of persistent NP Ag after immunization with AdNP. Importantly, depletion of alveolar macrophages after AdNP immunization resulted in significantly reduced numbers of NP-specific CD8+ TRMs in the lungs and airways. Combined, our results provide further insight to the mechanisms governing the enhanced longevity of Ag-specific CD8+ lung TRMs observed after immunization with recombinant Ad.
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Affiliation(s)
- Jenna L Lobby
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and
| | - Ida Uddbäck
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Christopher D Scharer
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and
| | - Tian Mi
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and
| | - Jeremy M Boss
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and
| | - Allan R Thomsen
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jan P Christensen
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jacob E Kohlmeier
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and
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25
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Li Y, You Z, Tang R, Ma X. Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function. Front Immunol 2022; 13:967055. [PMID: 36172356 PMCID: PMC9511135 DOI: 10.3389/fimmu.2022.967055] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Tissue-resident memory (TRM) T cells are a unique subset of memory T cells that are critical for the first line of defense against pathogens or antigens in peripheral non-lymphoid tissues such as liver, gut, and skin. Generally, TRM cells are well adapted to the local environment in a tissue-specific manner and typically do not circulate but persist in tissues, distinguishing them from other memory T cell lineages. There is strong evidence that liver TRM cells provide a robust adaptive immune response to potential threats. Indeed, the potent effector function of hepatic TRM cells makes it essential for chronic liver diseases, including viral and parasite infection, autoimmune liver diseases (AILD), nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) and liver transplantation. Manipulation of hepatic TRM cells might provide novel promising strategies for precision immunotherapy of chronic liver diseases. Here, we provide insights into the phenotype of hepatic TRM cells through surface markers, transcriptional profiles and effector functions, discuss the development of hepatic TRM cells in terms of cellular origin and factors affecting their development, analyze the role of hepatic TRM cells in chronic liver diseases, as well as share our perspectives on the current status of hepatic TRM cell research.
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26
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CD103 Expression on Regulatory and Follicular T Cells in Lymph Nodes, Bronchoalveolar Lavage Fluid and Peripheral Blood of Sarcoidosis Patients. Life (Basel) 2022; 12:life12050762. [PMID: 35629428 PMCID: PMC9146853 DOI: 10.3390/life12050762] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/12/2022] [Accepted: 05/19/2022] [Indexed: 11/26/2022] Open
Abstract
(1) Background: Sarcoidosis is a chronic multisystem disorder of unknown aetiology, driven by a T-cell mechanism allowing T-cell attachment and transmigration through the endothelium, and endorsed by the expression of an integrin alpha-E beta-7 (CD103). This study aimed to analyse the different distribution and compartmentalisation of CD103 expression on T cell subsets in BAL, peripheral blood mononuclear cells (PBMC) and lymph nodes (LLN) from sarcoidosis patients. (2) Patients: We consecutively and prospectively enrolled 14 sarcoidosis patients. We collected PBMC, LLN and BAL at the same time from all patients. Through flow cytometric analysis, we analysed the expression of CD103 on regulatory and follicular T cell subsets. (3) Results: All patients were in radiological Scadding stage II. The multivariate analysis found that the variables which most influenced the peripheral blood compartment were high CD8+ and low ThReg, CD8+CD103+ and Tfh cell percentages. A principal component analysis plot performed to distinguish LLN, BAL and PBMC showed that they separated on the basis of CD4+, CD4+CD103+, CD8+, CD8+CD103+, TcEffector, TcNaive, ThNaive, ThEffector, Threg, ThregCD103+, Tfh, TcfCXC5+ and CD4+CD103+/CD4+ with 65.96% of the total variance. (4) Conclusions: Our study is the first to report a link between the imbalance in circulating, alveolar and lymph node CD8+ and CD8+CD103+ T cells, ThReg, Tfh and ThNaive and the CD103+CD4+/CD4+ T cell ratio in the development of sarcoidosis. These findings shine a spotlight on the pathogenesis of sarcoidosis and may offer new predictors for diagnosis. Our study provides additional understanding for a personalised, and hopefully more effective treatment of sarcoidosis.
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27
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Richards AF, Torres-Velez FJ, Mantis NJ. Salmonella Uptake into Gut-Associated Lymphoid Tissues: Implications for Targeted Mucosal Vaccine Design and Delivery. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2410:305-324. [PMID: 34914054 DOI: 10.1007/978-1-0716-1884-4_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Peyer's patches are organized gut-associated lymphoid tissues (GALT) in the small intestine and the primary route by which particulate antigens, including viruses and bacteria, are sampled by the mucosal immune system. Antigen sampling occurs through M cells, a specialized epithelial cell type located in the follicle-associated epithelium (FAE) that overlie Peyer's patch lymphoid follicles. While Peyer's patches play an integral role in intestinal homeostasis, they are also a gateway by which enteric pathogens, like Salmonella enterica serovar Typhimurium (STm), cross the intestinal barrier. Once pathogens like STm gain access to the underlying network of mucosal dendritic cells and macrophages they can spread systemically. Thus, Peyer's patches are at the crossroads of mucosal immunity and intestinal pathogenesis. In this chapter, we provide detailed methods to assess STm entry into mouse Peyer's patch tissues. We describe Peyer's patch collection methods and provide strategies to enumerate bacterial uptake. We also detail a method for quantifying bacterial shedding from infected animals and provide an immunohistochemistry protocol for the localization of STm along the gastrointestinal tract and insight into pathogen transit in the presence of protective antibodies. While the protocols are written for STm, they are easily tailored to other enteric pathogens.
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Affiliation(s)
- Angelene F Richards
- Department of Biomedical Sciences, University at Albany School of Public Health, Albany, NY, USA.,Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - Fernando J Torres-Velez
- Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - Nicholas J Mantis
- Department of Biomedical Sciences, University at Albany School of Public Health, Albany, NY, USA. .,Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY, USA.
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28
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Ptasiewicz M, Grywalska E, Mertowska P, Korona-Głowniak I, Poniewierska-Baran A, Niedźwiedzka-Rystwej P, Chałas R. Armed to the Teeth-The Oral Mucosa Immunity System and Microbiota. Int J Mol Sci 2022; 23:882. [PMID: 35055069 PMCID: PMC8776045 DOI: 10.3390/ijms23020882] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 02/01/2023] Open
Abstract
The oral cavity is inhabited by a wide spectrum of microbial species, and their colonization is mostly based on commensalism. These microbes are part of the normal oral flora, but there are also opportunistic species that can cause oral and systemic diseases. Although there is a strong exposure to various microorganisms, the oral mucosa reduces the colonization of microorganisms with high rotation and secretion of various types of cytokines and antimicrobial proteins such as defensins. In some circumstances, the imbalance between normal oral flora and pathogenic flora may lead to a change in the ratio of commensalism to parasitism. Healthy oral mucosa has many important functions. Thanks to its integrity, it is impermeable to most microorganisms and constitutes a mechanical barrier against their penetration into tissues. Our study aims to present the role and composition of the oral cavity microbiota as well as defense mechanisms within the oral mucosa which allow for maintaining a balance between such numerous species of microorganisms. We highlight the specific aspects of the oral mucosa protecting barrier and discuss up-to-date information on the immune cell system that ensures microbiota balance. This study presents the latest data on specific tissue stimuli in the regulation of the immune system with particular emphasis on the resistance of the gingival barrier. Despite advances in understanding the mechanisms regulating the balance on the microorganism/host axis, more research is still needed on how the combination of these diverse signals is involved in the regulation of immunity at the oral mucosa barrier.
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Affiliation(s)
- Maja Ptasiewicz
- Department of Oral Medicine, Medical University of Lublin, 6 Chodzki Street, 20-093 Lublin, Poland; (M.P.); (R.C.)
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland;
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland;
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology, Medical University of Lublin, 20-093 Lublin, Poland;
| | | | | | - Renata Chałas
- Department of Oral Medicine, Medical University of Lublin, 6 Chodzki Street, 20-093 Lublin, Poland; (M.P.); (R.C.)
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Kim KH, Choi A, Kim SH, Song H, Jin S, Kim K, Jang J, Choi H, Jung YW. Neural-Cadherin Influences the Homing of Terminally Differentiated Memory CD8 T Cells to the Lymph Nodes and Bone Marrow. Mol Cells 2021; 44:795-804. [PMID: 34819396 PMCID: PMC8627834 DOI: 10.14348/molcells.2021.0137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 09/07/2021] [Accepted: 09/27/2021] [Indexed: 11/27/2022] Open
Abstract
Memory T (TM) cells play an important role in the long-term defense against pathogen reinvasion. However, it is still unclear how these cells receive the crucial signals necessary for their longevity and homeostatic turnover. To understand how TM cells receive these signals, we infected mice with lymphocytic choriomeningitis virus (LCMV) and examined the expression sites of neural cadherin (N-cadherin) by immunofluorescence microscopy. We found that N-cadherin was expressed in the surroundings of the white pulps of the spleen and medulla of lymph nodes (LNs). Moreover, TM cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1), a ligand of N-cadherin, were co-localized with N-cadherin+ cells in the spleen but not in LNs. We then blocked N-cadherin in vivo to investigate whether it regulates the formation or function of TM cells. The numbers of CD127hiCD62Lhi TM cells in the spleen of memory P14 chimeric mice declined when N-cadherin was blocked during the contraction phase, without functional impairment of these cells. In addition, when CD127loKLRG1hi TM cells were adoptively transferred into anti-N-cadherin-treated mice compared with control mice, the number of these cells was reduced in the bone marrow and LNs, without functional loss. Taken together, our results suggest that N-cadherin participates in the development of CD127hiCD62Lhi TM cells and homing of CD127loKLRG1hi TM cells to lymphoid organs.
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Affiliation(s)
- Kyong Hoon Kim
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Aryeong Choi
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Sang Hoon Kim
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Heonju Song
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Seohoon Jin
- Department of Applied Statistics, Korea University, Sejong 30019, Korea
| | - Kyungim Kim
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Jaebong Jang
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Hanbyeul Choi
- Department of Pharmacy, Korea University, Sejong 30019, Korea
| | - Yong Woo Jung
- Department of Pharmacy, Korea University, Sejong 30019, Korea
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30
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Abstract
Conventional CD4+ and CD8+ T lymphocytes comprise a mixture of naive and memory cells. Generation and survival of these T-cell subsets is under strict homeostatic control and reflects contact with self-major histocompatibility complex (MHC) and certain cytokines. Naive T cells arise in the thymus via T-cell receptor (TCR)-dependent positive selection to self-peptide/MHC complexes and are then maintained in the periphery through self-MHC interaction plus stimulation via interleukin-7 (IL-7). By contrast, memory T cells are largely MHC-independent for their survival but depend strongly on stimulation via cytokines. Whereas typical memory T cells are generated in response to foreign antigens, some arise spontaneously through contact of naive precursors with self-MHC ligands; we refer to these cells as memory-phenotype (MP) T cells. In this review, we discuss the generation and homeostasis of naive T cells and these two types of memory T cells, focusing on their relative interaction with MHC ligands and cytokines.
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Affiliation(s)
- Takeshi Kawabe
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Jaeu Yi
- Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Jonathan Sprent
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia
- St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia
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31
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Moraschi BF, Noronha IH, Ferreira CP, Cariste LM, Monteiro CB, Denapoli P, Vrechi T, Pereira GJS, Gazzinelli RT, Lannes-Vieira J, Rodrigues MM, Bortoluci KR, Vasconcelos JRC. Rapamycin Improves the Response of Effector and Memory CD8 + T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi. Front Cell Infect Microbiol 2021; 11:676183. [PMID: 34123875 PMCID: PMC8191465 DOI: 10.3389/fcimb.2021.676183] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/20/2021] [Indexed: 11/13/2022] Open
Abstract
Deficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8+ T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8+ T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8+ T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8+ T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8+ T-cells and the percentage of the polyfunctional population, which degranulated (CD107a+) and secreted both interferon gamma (IFNγ) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8+ T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8+ T-cell response.
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Affiliation(s)
- Barbara Ferri Moraschi
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Isaú Henrique Noronha
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Camila Pontes Ferreira
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Leonardo M. Cariste
- Recombinant Vaccines Laboratory, Department of Biosciences, Federal University of São Paulo, Santos, Brazil
| | - Caroline B. Monteiro
- Recombinant Vaccines Laboratory, Department of Biosciences, Federal University of São Paulo, Santos, Brazil
| | - Priscila Denapoli
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Talita Vrechi
- Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil
| | - Gustavo J. S. Pereira
- Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil
| | - Ricardo T. Gazzinelli
- René Rachou Research Center, Fiocruz, Belo Horizonte, Brazil
- Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States
| | - Joseli Lannes-Vieira
- Laboratoy of Biology of the Interactions, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
| | - Maurício M. Rodrigues
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Karina R. Bortoluci
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil
| | - José Ronnie C. Vasconcelos
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- Recombinant Vaccines Laboratory, Department of Biosciences, Federal University of São Paulo, Santos, Brazil
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Erazo AB, Wang N, Standke L, Semeniuk AD, Fülle L, Cengiz SC, Thiem M, Weighardt H, Strugnell RA, Förster I. CCL17-expressing dendritic cells in the intestine are preferentially infected by Salmonella but CCL17 plays a redundant role in systemic dissemination. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:891-904. [PMID: 33945673 PMCID: PMC8342217 DOI: 10.1002/iid3.445] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022]
Abstract
Introduction Salmonella spp. are a recognized and global cause of serious health issues from gastroenteritis to invasive disease. The mouse model of human typhoid fever, which uses Salmonella enterica serovar Typhimurium (STM) in susceptible mouse strains, has revealed that the bacteria gain access to extraintestinal tissues from the gastrointestinal tract to cause severe systemic disease. Previous analysis of the immune responses against Salmonella spp. revealed the crucial role played by dendritic cells (DCs) in carrying STM from the intestinal mucosa to the mesenteric lymph nodes (mLNs), a key site for antigen presentation and T cell activation. In this study, we investigated the influence of chemokine CCL17 on the dissemination of STM. Methods WT, CCL17/EGFP reporter, or CCL17‐deficient mice were infected orally with STM (SL1344) or mCherry‐expressing STM for 1–3 days. Colocalization of STM with CCL17‐expressing DCs in Peyer's patches (PP) and mLN was analyzed by fluorescence microscopy. In addition, DCs and myeloid cell populations from naïve and Salmonella‐infected mice were analyzed by flow cytometry. Bacterial load was determined in PP, mLN, spleen, and liver 1 and 3 days after infection. Results Histological analysis revealed that CCL17‐expressing cells are located in close proximity to STM in the dome area of PP. We show that, in mLN, STM were preferentially located within CCL17+ rather than CCL17− DCs, besides other mononuclear phagocytes, and identified the CD103+ CD11b− DC subset as the main STM‐carrying DC population in the intestine. STM infection triggered upregulation of CCL17 expression in specific intestinal DC subsets in a tissue‐specific manner. The dissemination of STM from the gut to the mLN, however, was only moderately influenced by the presence of CCL17. Conclusion CCL17‐expressing DCs were preferentially infected by Salmonella in the intestine in comparison to other DC. Nevertheless, the production of CCL17 was not essential for the early dissemination of Salmonella from the gut to systemic organs.
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Affiliation(s)
- Anna B Erazo
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.,Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Nancy Wang
- Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Lena Standke
- Department for Innate Immunity and Metaflammation, Institute of Innate Immunity, University Hospital Bonn, Medical Faculty, Bonn, Germany
| | - Adrian D Semeniuk
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.,Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Lorenz Fülle
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Sevgi C Cengiz
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Manja Thiem
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Heike Weighardt
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Richard A Strugnell
- Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Irmgard Förster
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
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Qiu Z, Chu TH, Sheridan BS. TGF-β: Many Paths to CD103 + CD8 T Cell Residency. Cells 2021; 10:cells10050989. [PMID: 33922441 PMCID: PMC8145941 DOI: 10.3390/cells10050989] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 12/24/2022] Open
Abstract
CD8 tissue-resident memory T (TRM) cells primarily reside in nonlymphoid tissues without recirculating and provide front-line protective immunity against infections and cancers. CD8 TRM cells can be generally divided into CD69+ CD103− TRM cells (referred to as CD103− TRM cells) and CD69+ CD103+ TRM cells (referred to as CD103+ TRM cells). TGF-β plays a critical role in the development and maintenance of CD103+ CD8 TRM cells. In this review, we summarize the current understanding of tissue-specific activation of TGF-β mediated by integrins and how it contributes to CD103+ CD8 TRM cell development and maintenance. Furthermore, we discuss the underlying mechanisms utilized by TGF-β to regulate the development and maintenance of CD103+ CD8 TRM cells. Overall, this review highlights the importance of TGF-β in regulating this unique subset of memory CD8 T cells that may shed light on improving vaccine design to target this population.
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34
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Tokura Y, Phadungsaksawasdi P, Kurihara K, Fujiyama T, Honda T. Pathophysiology of Skin Resident Memory T Cells. Front Immunol 2021; 11:618897. [PMID: 33633737 PMCID: PMC7901930 DOI: 10.3389/fimmu.2020.618897] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022] Open
Abstract
Tissue resident memory T (TRM) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin TRM cells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8+CD69+CD103+ TRM cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-β are required for the formation of long-lived TRM cell population in skin. Skin TRM cells engage virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. Secondary TRM cell populations are derived from pre-existing TRM cells and newly recruited TRM precursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8+ TRM cells at challenged site. Skin TRM cells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these TRM cells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8+CD103+CD49a- TRM cells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8+CD103+CD49a+ TRM cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin TRM cells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8+ TRM cells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed TRM cells. CD8+ CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8+ TRM cells. This review will discuss the current understanding of skin TRM biology and their contribution to skin homeostasis and diseases.
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Affiliation(s)
- Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Department of Cellular & Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | - Kazuo Kurihara
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Toshiharu Fujiyama
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tetsuya Honda
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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35
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Özgül Özdemir RB, Özdemir AT, Kırmaz C, Eker Sarıboyacı A, Karaöz E, Erman G, Vatansever HS, Mete Gökmen N. Age-related changes in the immunomodulatory effects of human dental pulp derived mesenchymal stem cells on the CD4 + T cell subsets. Cytokine 2020; 138:155367. [PMID: 33223447 DOI: 10.1016/j.cyto.2020.155367] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/08/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells. The effects of the aging on these abilities of MSCs have not been adequately clarified. In this study, alterations in immunomodulatory abilities of MSCs caused by aging were investigated. For this, dental pulp (DP) MSCs and peripheral blood mononuclear cells (PBMCs) of elderly and young donors were co-cultured age-matched and cross. We detected that the effects of DP-MSCs on Th1 and Th2 cells and their specific cytokines IFN-γ and IL-4 are not affected by aging. However, we observed that young and elderly DP-MSCs have different effects on Th17 and Treg cells. Th17 frequencies of young and elderly PBMCs were significantly increased only by young DP-MSCs, in contrast, Treg frequencies were significantly increased by elderly DP-MSCs. IL-6, IL-17a and HGF levels of both young and elderly PBMCs showed a significant increase only by young DP-MSCs, but TGF-β levels were significantly increased only by elderly DP-MSCs. The oral cavity is home to a rich microflora. The interactions of dental tissues with this microflora can lead them to acquire different epigenetic modifications. Aging can affect the microflora composition of the oral cavity and change this process in different directions. According to our findings, DP-MSCs are effective cells in the regulation of CD4+ T cells, and their effects on Th1 and Th2 cells were not affected by aging. However, pleiotropic molecules IL-6 and HGF expressions, which are important in dental and bone tissue regeneration, decreased significantly in elderly DP-MSCs. This situation may have indirectly made a difference in the modulation effects of young and elderly DP-MSCs on the Th17 and Treg cells.
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Affiliation(s)
| | - Alper Tunga Özdemir
- Merkezefendi State Hospital, Department of Medical Biochemistry, Manisa, Turkey.
| | - Cengiz Kırmaz
- Manisa Celal Bayar University, Medical School, Department of Internal Medicine, Division of Allergy and Clinical Immunology, Manisa, Turkey
| | - Ayla Eker Sarıboyacı
- Eskisehir Osmangazi University, Cellular Therapy and Stem Cell Production Application and Research Center, Eskisehir, Turkey
| | - Erdal Karaöz
- Liv Hospital, Center of Regenerative Medicine and Stem Cell Research, Istanbul, Turkey; Istinye University, Medical School, Department of Histology and Embryology, Istanbul, Turkey
| | - Gülay Erman
- Sakarya University, Medical School, Department of Medical Biology, Sakarya, Turkey
| | - H Seda Vatansever
- Manisa Celal Bayar University, Medical School, Department of Histology and Embryology, Manisa, Turkey; Near East University, Experimental Health Science Research Center, Nicosia, North Cyprus, Turkey
| | - Nihal Mete Gökmen
- Ege University, Medical School, Department of Internal Medicine, Division of Immunology, Izmir, Turkey
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Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood Adv 2020; 3:4136-4146. [PMID: 31821456 DOI: 10.1182/bloodadvances.2019000893] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/31/2019] [Indexed: 12/21/2022] Open
Abstract
Acute graft-versus-host disease (aGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab could help prevent aGVHD by inhibiting the migration of both naive and activated lymphocytes into gut-associated lymphoid tissues and the lamina propria. We carried out a phase 1b, open-label, dose-finding study in adults undergoing allo-HSCT to evaluate the tolerability, safety, and pharmacokinetics of vedolizumab, and its effectiveness in reducing aGVHD. IV vedolizumab was administered on day -1, +13, and +42 with respect to allo-HSCT, starting at 75 mg and with dose escalation guided by tolerability and pharmacokinetics. A total of 24 participants was enrolled, and no dose-limiting toxicities were observed in either the 75-mg cohort (n = 3) or the dose-escalated 300-mg cohort (n = 21). Treatment-emergent adverse events related to vedolizumab occurred in 8 participants. Overall, 4 deaths occurred during the 12 months following allo-HSCT. No participants in the 75-mg cohort developed modified Glucksberg grade II to IV aGVHD by 100 days after allo-HSCT. Four participants (19.0%) in the 300-mg cohort developed grade II to IV aGVHD by 100 days after allo-HSCT, including 3 participants who developed stage 1 aGVHD of the lower-intestinal tract. Vedolizumab IV 300 mg was well tolerated as aGVHD prevention, and the incidence of overall and lower-intestinal aGVHD was low. These findings support further evaluation of vedolizumab in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02728895.
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Saraf S, Jain S, Sahoo RN, Mallick S. Present Scenario of M-Cell Targeting Ligands for Oral Mucosal Immunization. Curr Drug Targets 2020; 21:1276-1284. [DOI: 10.2174/1389450121666200609113252] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/18/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
The immune system plays an important role in the prevention of infection and forms the
first line of defense against pathogen attack. Delivering of antigen through mucosal route may elicit
mucosal immune system as the mucosal surface is the most common site of pathogen entry. Mucosal
immune system will be capable to counter pathogen at mucosal surface. Oral mucosal immunization
opens the ways to deliver antigens at gut-associated lymphoid tissue. This can elicit both local and
systemic immune response. Mucosal vaccines are economical, highly accessible, non parenteral delivery
and capacity to produce mass immunization at the time of pandemics. To deliver antigens on the
mucosal surface of the gastrointestinal tract, the immune system relies on specialized epithelial cell
i.e. Microfold (M)-cell. An approach to exploit the targeting specific receptors on M-cell for entry of
antigens has made a breakthrough in vaccine development. In this review, various strategies have been
discussed for the possible entry of antigens through M-cells and an approach to increase the uptake
and efficacy of vaccines for oral mucosal immunization.
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Affiliation(s)
- Surendra Saraf
- School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar-751030, Orissa, India
| | - Shailesh Jain
- Dean, Faculty of Pharmacy and Pharmaceutical Sciences at Madhyanchal Professional University Bhopal (MP), India
| | - Rudra Narayan Sahoo
- School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar-751030, Orissa, India
| | - Subrata Mallick
- School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar-751030, Orissa, India
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38
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Imperato JN, Xu D, Romagnoli PA, Qiu Z, Perez P, Khairallah C, Pham QM, Andrusaite A, Bravo-Blas A, Milling SWF, Lefrancois L, Khanna KM, Puddington L, Sheridan BS. Mucosal CD8 T Cell Responses Are Shaped by Batf3-DC After Foodborne Listeria monocytogenes Infection. Front Immunol 2020; 11:575967. [PMID: 33042159 PMCID: PMC7518468 DOI: 10.3389/fimmu.2020.575967] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/24/2020] [Indexed: 12/24/2022] Open
Abstract
While immune responses have been rigorously examined after intravenous Listeria monocytogenes (Lm) infection, less is understood about its dissemination from the intestines or the induction of adaptive immunity after more physiologic models of foodborne infection. Consequently, this study focused on early events in the intestinal mucosa and draining mesenteric lymph nodes (MLN) using foodborne infection of mice with Lm modified to invade murine intestinal epithelium (InlAMLm). InlAMLm trafficked intracellularly from the intestines to the MLN and were associated with Batf3-independent dendritic cells (DC) in the lymphatics. Consistent with this, InlAMLm initially disseminated from the gut to the MLN normally in Batf3–/– mice. Activated migratory DC accumulated in the MLN by 3 days post-infection and surrounded foci of InlAMLm. At this time Batf3–/– mice displayed reduced InlAMLm burdens, implicating cDC1 in maximal bacterial accumulation in the MLN. Batf3–/– mice also exhibited profound defects in the induction and gut-homing of InlAMLm-specific effector CD8 T cells. Restoration of pathogen burden did not rescue antigen-specific CD8 T cell responses in Batf3–/– mice, indicating a critical role for Batf3 in generating anti-InlAMLm immunity following foodborne infection. Collectively, these data suggest that DC play diverse, dynamic roles in the early events following foodborne InlAMLm infection and in driving the establishment of intestinal Lm-specific effector T cells.
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Affiliation(s)
- Jessica Nancy Imperato
- Department of Microbiology and Immunology, Center for Infectious Diseases, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Daqi Xu
- Department of Immunology, UConn Health, Farmington, CT, United States
| | - Pablo A Romagnoli
- Centro de Investigacion en Medicina Traslacional Severo Amuchastegui, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
| | - Zhijuan Qiu
- Department of Microbiology and Immunology, Center for Infectious Diseases, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Pedro Perez
- Department of Microbiology and Immunology, Center for Infectious Diseases, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Camille Khairallah
- Department of Microbiology and Immunology, Center for Infectious Diseases, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Quynh-Mai Pham
- Department of Immunology, UConn Health, Farmington, CT, United States
| | - Anna Andrusaite
- Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | | | - Simon W F Milling
- Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Leo Lefrancois
- Department of Immunology, UConn Health, Farmington, CT, United States
| | - Kamal M Khanna
- Department of Microbiology, New York University, New York City, NY, United States
| | - Lynn Puddington
- Department of Immunology, UConn Health, Farmington, CT, United States
| | - Brian S Sheridan
- Department of Microbiology and Immunology, Center for Infectious Diseases, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
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Li W, Zhang L. Rewiring Mitochondrial Metabolism for CD8 + T Cell Memory Formation and Effective Cancer Immunotherapy. Front Immunol 2020; 11:1834. [PMID: 32983095 PMCID: PMC7481383 DOI: 10.3389/fimmu.2020.01834] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 07/08/2020] [Indexed: 11/13/2022] Open
Abstract
Memory T cells persist for long term to mediate robust recall response upon rechallenging with previous encountered pathogens. The memory T cell pool is highly heterogeneous based on distinct phenotypic, functional, and locational properties, and contains discrete subsets, which contribute to diverse immune responses. In this mini-review, we will briefly discuss the distinct subsets of memory T cells and then focus on mitochondria-related metabolic and epigenetic regulations of CD8+ T cell memory formation. In particular, we discuss many aspects of mitochondrial quality control systems (biogenesis, dynamics, etc.) in regulating CD8+ T cell fate decision and antitumor immunity. Importantly, targeting mitochondrial metabolism to boost T cell memory formation and metabolic fitness might represent an attractive strategy to improve cancer immunotherapy including CAR-T therapy.
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Affiliation(s)
- Wenhui Li
- Suzhou Institute of Systems Medicine, Suzhou, China.,Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lianjun Zhang
- Suzhou Institute of Systems Medicine, Suzhou, China.,Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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40
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Chen P, Ming S, Lao J, Li C, Wang H, Xiong L, Zhang S, Liang Z, Niu X, Deng S, Geng L, Wu M, Wu Y, Gong S. CD103 Promotes the Pro-inflammatory Response of Gastric Resident CD4 + T Cell in Helicobacter pylori-Positive Gastritis. Front Cell Infect Microbiol 2020; 10:436. [PMID: 32974219 PMCID: PMC7472738 DOI: 10.3389/fcimb.2020.00436] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/16/2020] [Indexed: 12/12/2022] Open
Abstract
CD103 is considered as a surface marker for the resident immune cells. However, little is known about the intrinsic function of CD103 in infection and inflammation. In this study, we found that CD103 was highly expressed in CD4+T cells of the gastric mucosa from patients with H. pylori-positive gastritis. Mucosal resident CD103+CD4+T cells exhibited an increase in the CD45RO+CCR7− effector memory phenotype and high expression of the chemokine receptors CXCR3 and CCR9 compared with those in CD103−CD4+T cells. An In vitro coculture study demonstrated that H. pylori-specific antigen CagA/VacA-primed dendritic cells (DCs) induced proliferation and IFN-γ, TNF as well as IL-17 production by CD103+CD4+T cells from patients with H. pylori-positive gastritis, while blocking CD103 with a neutralizing antibody reduced proliferation and IFN-γ, TNF, and IL-17 production by CD103+CD4+T cells cocultured with DCs. Moreover, immunoprecipitation revealed that CD103 interacted with TCR α/β and CD3ζ, and activation of CD103 enhanced the phosphorylation of ZAP70 induced by the TCR signal. Finally, increased T-bet and Blimp1 levels were also observed in CD103+CD4+T cells, and activating CD103 increased T-bet and Blimp1 expression in CD4+T cells. Our results explored the intrinsic function of CD103 in gastric T cells from patients with H. pylori-positive gastritis, which may provide a therapeutic target for the treatment of gastritis.
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Affiliation(s)
- Peiyu Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Siqi Ming
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Juanfeng Lao
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chunna Li
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongli Wang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Liya Xiong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Shunxian Zhang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Zibin Liang
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoli Niu
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Simei Deng
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Minhao Wu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China.,Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongjian Wu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China.,Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
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Abstract
In mammals, adaptive immunity is mediated by a broadly diverse repertoire of naive B and T lymphocytes that recirculate between secondary lymphoid organs. Initial antigen exposure promotes lymphocyte clonal expansion and differentiation, including the formation of memory cells. Antigen-specific memory cells are maintained at higher frequencies than their naive counterparts and have different functional and homing abilities. Importantly, a subset of memory cells, known as tissue-resident memory cells, is maintained without recirculating in nonlymphoid tissues, often at barrier surfaces, where they can be reactivated by antigen and rapidly perform effector functions that help protect the tissue in which they reside. Although antigen-experienced B cells are abundant at many barrier surfaces, their characterization as tissue-resident memory B (BRM) cells is not well developed. In this study, we describe the characteristics of memory B cells in various locations and discuss their possible contributions to immunity and homeostasis as bona fide BRM cells.
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Affiliation(s)
- S. Rameeza Allie
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Troy D. Randall
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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42
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Haddad LB, Swaims-Kohlmeier A, Mehta CC, Haaland RE, Brown NL, Sheth AN, Chien H, Titanji K, Achilles SL, Lupo D, Hart CE, Ofotokun I. Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood. PLoS One 2020; 15:e0230473. [PMID: 32214321 PMCID: PMC7098611 DOI: 10.1371/journal.pone.0230473] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 02/28/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND While prior epidemiologic studies have suggested that injectable progestin-based contraceptive depot medroxyprogesterone acetate (DMPA) use may increase a woman's risk of acquiring HIV, recent data have suggested that DMPA users may be at a similar risk for HIV acquisition as users of the copper intrauterine device and levonorgestrel implant. Use of the etonogestrel Implant (Eng-Implant) is increasing but there are currently no studies evaluating its effect on HIV acquisition risk. OBJECTIVE Evaluate the potential effect of the Eng-Implant use on HIV acquisition risk by analyzing HIV target cells and cytokine profiles in the lower genital tract and blood of adult premenopausal HIV-negative women using the Eng-Implant. METHODS We prospectively obtained paired cervicovaginal lavage (CVL) and blood samples at 4 study visits over 16 weeks from women between ages 18-45, with normal menses (22-35 day intervals), HIV uninfected with no recent hormonal contraceptive or copper intrauterine device (IUD) use, no clinical signs of a sexually transmitted infection at enrollment and who were medically eligible to initiate Eng-Implant. Participants attended pre-Eng-Implant study visits (week -2, week 0) with the Eng-Implant inserted at the end of the week 0 study visit and returned for study visits at weeks 12 and 14. Genital tract leukocytes (enriched from CVL) and peripheral blood mononuclear cells (PBMC) from the study visits were evaluated for markers of activation (CD38, HLA-DR), retention (CD103) and trafficking (CCR7) on HIV target cells (CCR5+CD4+ T cells) using multicolor flow cytometry. Cytokines and chemokines in the CVL supernatant and blood plasma were measured in a Luminex assay. We estimated and compared study endpoints among the samples collected before and after contraception initiation with repeated-measures analyses using linear mixed models. RESULTS Fifteen of 18 women who received an Eng-Implant completed all 4 study visits. The percentage of CD4+ T cells in CVL was not increased after implant placement but the percentage of CD4+ T cells expressing the HIV co-receptor CCR5 did increase after implant placement (p = 0.02). In addition, the percentage of central memory CD4+ T-cells (CCR7+) in CVL increased after implant placement (p = 0.004). The percentage of CVL CD4+, CCR5+ HIV target cells expressing activation markers after implant placement was either reduced (HLA-DR+, p = 0.01) or unchanged (CD38+, p = 0.45). Most CVL cytokine and chemokine concentrations were not significantly different after implant placement except for a higher level of the soluble lymphocyte activation marker (sCD40L; p = 0.04) and lower levels of IL12p70 (p = 0.02) and G-CSF (p<0.001). In systemic blood, none of the changes noted in CVL after implant placement occurred except for decreases in the percentage CD4 T-cells expressing HLA-DR+ T cells (p = 0.006) and G-CSF (p = 0.02). CONCLUSIONS Eng-Implant use was associated with a moderate increase in the availability of HIV target cells in the genital tract, however the percentage of these cells that were activated did not increase and there were minimal shifts in the overall immune environment. Given the mixed nature of these findings, it is unclear if these implant-induced changes alter HIV risk.
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Affiliation(s)
- Lisa B. Haddad
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Alison Swaims-Kohlmeier
- Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - C. Christina Mehta
- Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, Georgia, United States of America
| | - Richard E. Haaland
- Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Nakita L. Brown
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia
- Grady Healthcare System, Atlanta, Georgia, United States of America
| | - Anandi N. Sheth
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia
- Grady Healthcare System, Atlanta, Georgia, United States of America
| | - Hsin Chien
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia
- Grady Healthcare System, Atlanta, Georgia, United States of America
| | - Kehmia Titanji
- Department of Medicine, Division of Endocrinology, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Sharon L. Achilles
- Department of Obstetrics, University of Pittsburg, Gynecology and Reproductive Sciences, Pittsburg, Pennsylvania, United States of America
| | - Davis Lupo
- Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Clyde E. Hart
- Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Igho Ofotokun
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia
- Grady Healthcare System, Atlanta, Georgia, United States of America
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Asialo GM1-positive liver-resident CD8 T cells that express CD44 and LFA-1 are essential for immune clearance of hepatitis B virus. Cell Mol Immunol 2020; 18:1772-1782. [PMID: 32111985 DOI: 10.1038/s41423-020-0376-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 02/02/2020] [Indexed: 11/08/2022] Open
Abstract
Persistent hepatitis B virus (HBV) infection results in chronic liver diseases that may progress to chronic hepatitis, liver cirrhosis, and subsequent hepatocellular carcinoma. Previous studies demonstrated that adaptive immunity, in particular CD8 T cells, is critical in HBV elimination. Recent studies have revealed a distinct tissue-localized T cell lineage, tissue-resident memory (TRM) cells, that is crucial for protective immunity in peripheral tissues. In this study, we showed that treatment with an anti-asialo GM1 (ASGM1) antibody (Ab), which depletes NK cells, led to impairment of HBV clearance in a mouse animal model. Unexpectedly, the ability to clear HBV was not significantly impaired in NFIL3 KO mice, which are deficient in NK cells, implying that other non-NK ASGM1-positive immune cells mediate HBV clearance. We isolated intrahepatic ASGM1-positive cells from NFIL3 KO mice and analyzed the immune phenotype of these cells. Our results demonstrated a distinct population of CD44+ LFA-1hi CD8 T cells that were the major intrahepatic ASGM1-positive immune cells in NFIL3 KO mice. Importantly, transcriptome analysis revealed that these ASGM1-positive CD8 T cells had distinct gene profiles and shared a similar core gene signature with TRM cells. In addition to both transcriptional and phenotypic liver residency characteristics, ASGM1-positive CD8 T cells were able to home to and be retained in the liver after adoptive transfer. Taken together, our study results indicate that these ASGM1-positive liver-resident CD8 T cells are the major effector immune cells mediating anti-HBV immunity.
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44
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Memory CD4 + T Cells in Immunity and Autoimmune Diseases. Cells 2020; 9:cells9030531. [PMID: 32106536 PMCID: PMC7140455 DOI: 10.3390/cells9030531] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/20/2020] [Accepted: 02/20/2020] [Indexed: 12/26/2022] Open
Abstract
CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4+ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4+ tissue-resident memory T cells and of CD4+ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4+ T cell-mediated autoimmune diseases.
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45
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Sais M, Barroeta AC, López-Colom P, Nofrarías M, Majó N, Lopez-Ulibarri R, Pérez Calvo E, Martín-Orúe SM. Evaluation of dietary supplementation of a novel microbial muramidase on gastrointestinal functionality and growth performance in broiler chickens. Poult Sci 2020; 99:235-245. [PMID: 32416807 PMCID: PMC7587705 DOI: 10.3382/ps/pez466] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 08/05/2019] [Indexed: 12/17/2022] Open
Abstract
This study was conducted to assess the effect of dietary supplementation of Muramidase 007 to broiler chickens on gastrointestinal functionality, evaluating growth performance, apparent ileal digestibility, intestinal histomorphology, vitamin A in plasma and cecal microbiota. A total of 480 one-day male chicks (Ross 308) were distributed in 16 pens allocated in 2 experimental diets: the control diet (CTR) without feed enzymes, coccidiostat or growth promoters, and the experimental diet (MUR): CTR supplemented with 35,000 units (LSU(F))/kg of the Muramidase 007. Digesta and tissue samples were obtained on days 9 and 36 of the study. A lower feed conversion ratio was observed in the MUR treatment. Apparent ileal digestibility of DM, organic matter and energy were improved by Muramidase 007. It was also observed that MUR improved digestibility of total fatty acids, mono-unsaturated fatty acids and poly-unsaturated fatty acids, and content of vitamin A in plasma at day 9 (P < 0.05). Histomorphological analysis of jejunum samples revealed no differences in the villus height or crypt depth; but a higher number of goblet cells and intraepithelial lymphocytes at day 36 with MUR. No differences were observed in plate counts of enterobacteria or Lactobacillus along the gastrointestinal tract, neither on the cecal short-chain fatty acids. An statistical trend was observed for reduction of cecal clostridia at day 9 for MUR. Analysis of cecal microbiota structure by 16S rRNA gene sequencing revealed relevant changes correlated to age. At day 9, broilers receiving MUR showed decreased alpha diversity compared to CTR that was not detected at day 36. Changes in specific taxonomic groups with an increase in Lactobacillus genus were identified. In conclusion, evaluation of the variables in this study indicates that dietary Muramidase 007 contributes to improve feed conversation ratio and gastrointestinal function in broiler chickens. Effects could have been mediated by slight shifts observed in the intestinal microbiota. More studies are guaranteed to fully understand the mechanisms involved.
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Affiliation(s)
- Mounira Sais
- Animal Nutrition and Welfare Service. Animal and Food Science Department, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Ana C Barroeta
- Animal Nutrition and Welfare Service. Animal and Food Science Department, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Paola López-Colom
- Animal Nutrition and Welfare Service. Animal and Food Science Department, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Miquel Nofrarías
- IRTA, Centre de Recerca en Sanitat Animal (CReSA, UAB-IRTA), Campus de la Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Natàlia Majó
- IRTA, Centre de Recerca en Sanitat Animal (CReSA, UAB-IRTA), Campus de la Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
| | - Rual Lopez-Ulibarri
- DSM Nutritional Products Ltd, Nutrition Innovation Center - ANH, 4303 Kaiseraugst, Switzerland
| | - Estefanía Pérez Calvo
- DSM Nutritional Products Ltd, Nutrition Innovation Center - ANH, 68128 Village Neuf, France
| | - Susana M Martín-Orúe
- Animal Nutrition and Welfare Service. Animal and Food Science Department, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.
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Devaux CA, Mezouar S, Mege JL. The E-Cadherin Cleavage Associated to Pathogenic Bacteria Infections Can Favor Bacterial Invasion and Transmigration, Dysregulation of the Immune Response and Cancer Induction in Humans. Front Microbiol 2019; 10:2598. [PMID: 31781079 PMCID: PMC6857109 DOI: 10.3389/fmicb.2019.02598] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 10/25/2019] [Indexed: 12/21/2022] Open
Abstract
Once bound to the epithelium, pathogenic bacteria have to cross epithelial barriers to invade their human host. In order to achieve this goal, they have to destroy the adherens junctions insured by cell adhesion molecules (CAM), such as E-cadherin (E-cad). The invasive bacteria use more or less sophisticated mechanisms aimed to deregulate CAM genes expression or to modulate the cell-surface expression of CAM proteins, which are otherwise rigorously regulated by a molecular crosstalk essential for homeostasis. Apart from the repression of CAM genes, a drastic decrease in adhesion molecules on human epithelial cells can be obtained by induction of eukaryotic endoproteases named sheddases or through synthesis of their own (prokaryotic) sheddases. Cleavage of CAM by sheddases results in the release of soluble forms of CAM. The overexpression of soluble CAM in body fluids can trigger inflammation and pro-carcinogenic programming leading to tumor induction and metastasis. In addition, the reduction of the surface expression of E-cad on epithelia could be accompanied by an alteration of the anti-bacterial and anti-tumoral immune responses. This immune response dysfunction is likely to occur through the deregulation of immune cells homing, which is controlled at the level of E-cad interaction by surface molecules αE integrin (CD103) and lectin receptor KLRG1. In this review, we highlight the central role of CAM cell-surface expression during pathogenic microbial invasion, with a particular focus on bacterial-induced cleavage of E-cad. We revisit herein the rapidly growing body of evidence indicating that high levels of soluble E-cad (sE-cad) in patients’ sera could serve as biomarker of bacterial-induced diseases.
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Affiliation(s)
- Christian A Devaux
- IRD, MEPHI, APHM, Aix-Marseille University, Marseille, France.,CNRS, Institute of Biological Science (INSB), Marseille, France.,Institut Hospitalo-Universitaire (IHU)-Mediterranee Infection, Marseille, France
| | - Soraya Mezouar
- IRD, MEPHI, APHM, Aix-Marseille University, Marseille, France.,Institut Hospitalo-Universitaire (IHU)-Mediterranee Infection, Marseille, France
| | - Jean-Louis Mege
- IRD, MEPHI, APHM, Aix-Marseille University, Marseille, France.,Institut Hospitalo-Universitaire (IHU)-Mediterranee Infection, Marseille, France.,APHM, UF Immunology Department, Marseille, France
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47
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Chen L, Shen Z. Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders. Cell Mol Immunol 2019; 17:64-75. [PMID: 31595056 DOI: 10.1038/s41423-019-0291-4] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 08/25/2019] [Indexed: 11/09/2022] Open
Abstract
The skin is the largest organ of the body. The establishment of immunological memory in the skin is a crucial component of the adaptive immune response. Once naive T cells are activated by antigen-presenting cells, a small fraction of them differentiate into precursor memory T cells. These precursor cells ultimately develop into several subsets of memory T cells, including central memory T (TCM) cells, effector memory T (TEM) cells, and tissue resident memory T (TRM) cells. TRM cells have a unique transcriptional profile, and their most striking characteristics are their long-term survival (longevity) and low migration in peripheral tissues, including the skin. Under physiological conditions, TRM cells that reside in the skin can respond rapidly to pathogenic challenges. However, there is emerging evidence to support the vital role of TRM cells in the recurrence of chronic inflammatory skin disorders, including psoriasis, vitiligo, and fixed drug eruption, under pathological or uncontrolled conditions. Clarifying and characterizing the mechanisms that are involved in skin TRM cells will help provide promising strategies for reducing the frequency and magnitude of skin inflammation recurrence. Here, we discuss recent insights into the generation, homing, retention, and survival of TRM cells and share our perspectives on the biological characteristics of TRM cells in the recurrence of inflammatory skin disorders.
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Affiliation(s)
- Ling Chen
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhu Shen
- Department of Dermatology, Institute of Dermatology and Venereology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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48
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Miller CJ, Veazey RS. T Cells in the Female Reproductive Tract Can Both Block and Facilitate HIV Transmission. ACTA ACUST UNITED AC 2019; 15:36-40. [PMID: 31431806 DOI: 10.2174/1573395514666180807113928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Because HIV is sexually transmitted, there is considerable interest in defining the nature of anti-HIV immunity in the female reproductive tract (FRT) and in developing ways to elicit antiviral immunity in the FRT through vaccination. Although it is assumed that the mucosal immune system of the FRT is of central importance for protection against sexually transmitted diseases, including HIV, this arm of the immune system has only recently been studied. Here we provide a brief review of the role of T cells in the FRT in blocking and facilitating HIV transmission.
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Affiliation(s)
- Christopher J Miller
- Professor of Pathology, Microbiology, and Immunology, Center for Comparative Medicine.,California National Primate Research Center, University of California, Davis, Davis, Ca, 95616
| | - Ronald S Veazey
- Professor of Pathology and Laboratory Medicine, Tulane University School of Medicine.,Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433
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49
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Menzies FM, Oldham RS, Waddell C, Nelson SM, Nibbs RJB. A Comprehensive Profile of Chemokine Gene Expression in the Tissues of the Female Reproductive Tract in Mice. Immunol Invest 2019; 49:264-286. [PMID: 31429329 DOI: 10.1080/08820139.2019.1655573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Homeostatic leukocyte trafficking into and within the female reproductive tract (FRT) contributes to fertility and reproductive health. It is unclear how this process is regulated in the anatomically distinct reproductive tissues, or whether the genes involved are affected by cyclical changes in reproductive hormones. In tissues such as skin and intestine, mouse studies have defined evolutionarily conserved molecular mechanisms for tissue-specific homing, interstitial positioning, and leukocyte egress. Chemokine family members are invariably involved, with the chemokine expression profile of a tissue regulating leukocyte content. Reproductive tissues (ovary, vagina, cervix, uterine horn) of 8 week old virgin female C57BL/6 mice (n = 20) were collected, and expression of mRNA for leukocyte markers and chemokines conducted by qPCR. Lymphocytic and myeloid cell populations within the uterus, cervix, bone marrow and PALN from virgin C57BL/6 mice were determined by flow cytometric analysis. Variation in leukocyte content between reproductive tissues is evident, with the uterus and cervix containing complex mixtures of lymphocytes and myeloid cells. Twenty-six chemokine genes are expressed in the FRT, many by several component tissues, some preferentially by one. Most striking are Xcl1 and Ccl28, which are restricted to the uterus. Ccl20 and genes encoding CXCR2 ligands are primarily transcribed in cervix and vagina. Ovary shows the lowest expression of most chemokine genes, with the notable exception of Ccl21 and Ccl27. We also identify eight chemokines in the vagina whose expression fluctuates substantially across the oestrous cycle. These data reveal complex chemokine networks within the FRT, and provide a framework for future studies of homeostatic leukocyte trafficking into and within these tissues.Abbreviations: BM: bone marrow; DC: dendritic cell; DN: double negative; FRT: female reproductive tract; FSC: forward scatter; NK: natural killer; PALN: para-aortic lymph node; SSC: side scatter; Tregs: regulatory T cells.
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Affiliation(s)
- Fiona M Menzies
- School of Health & Life Science, University of the West of Scotland, Paisley, UK.,Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Rachel S Oldham
- Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.,Institute of Infection, Immunity & Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Carolann Waddell
- Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Scott M Nelson
- Obstetrics & Gynaecology, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Robert J B Nibbs
- Institute of Infection, Immunity & Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
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50
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Figueredo CM, Lira-Junior R, Love RM. T and B Cells in Periodontal Disease: New Functions in A Complex Scenario. Int J Mol Sci 2019; 20:ijms20163949. [PMID: 31416146 PMCID: PMC6720661 DOI: 10.3390/ijms20163949] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/09/2019] [Accepted: 08/13/2019] [Indexed: 12/19/2022] Open
Abstract
Periodontal disease is characterised by a dense inflammatory infiltrate in the connective tissue. When the resolution is not achieved, the activation of T and B cells is crucial in controlling chronic inflammation through constitutive cytokine secretion and modulation of osteoclastogenesis. The present narrative review aims to overview the recent findings of the importance of T and B cell subsets, as well as their cytokine expression, in the pathogenesis of the periodontal disease. T regulatory (Treg), CD8+ T, and tissue-resident γδ T cells are important to the maintenance of gingival homeostasis. In inflamed gingiva, however, the secretion of IL-17 and secreted osteoclastogenic factor of activated T cells (SOFAT) by activated T cells is crucial to induce osteoclastogenesis via RANKL activation. Moreover, the capacity of mucosal-associated invariant T cells (MAIT cells) to produce cytokines, such as IFN-γ, TNF-α, and IL-17, might indicate a critical role of such cells in the disease pathogenesis. Regarding B cells, low levels of memory B cells in clinically healthy periodontium seem to be important to avoid bone loss due to the subclinical inflammation that occurs. On the other hand, they can exacerbate alveolar bone loss in a receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent manner and affect the severity of periodontitis. In conclusion, several new functions have been discovered and added to the complex knowledge about T and B cells, such as possible new functions for Tregs, the role of SOFAT, and MAIT cells, as well as B cells activating RANKL. The activation of distinct T and B cell subtypes is decisive in defining whether the inflammatory lesion will stabilise as chronic gingivitis or will progress to a tissue destructive periodontitis.
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Affiliation(s)
- C M Figueredo
- School of Dentistry and Oral Health, Griffith University, Queensland 4222, Australia.
- Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
| | - R Lira-Junior
- Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, 141 04 Stockholm, Sweden
| | - R M Love
- School of Dentistry and Oral Health, Griffith University, Queensland 4222, Australia
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