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1
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Hilt ZT, Charles W, Ali T, Smith CV, Zhang S, Wesnak SP, Smith NL, Rudd BD. Cutting Edge: Retinoic Acid Promotes Brain-homing of CD8+ T Cells during Congenital Cytomegalovirus Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:933-939. [PMID: 39132993 PMCID: PMC11529782 DOI: 10.4049/jimmunol.2400150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 07/17/2024] [Indexed: 08/13/2024]
Abstract
The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.
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Affiliation(s)
- Zachary T. Hilt
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Wisler Charles
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Taha Ali
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Casey V. Smith
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Shide Zhang
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Samantha P. Wesnak
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Norah L. Smith
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Brian D. Rudd
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
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2
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Gavil NV, Cheng K, Masopust D. Resident memory T cells and cancer. Immunity 2024; 57:1734-1751. [PMID: 39142275 PMCID: PMC11529779 DOI: 10.1016/j.immuni.2024.06.017] [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: 03/04/2024] [Revised: 05/04/2024] [Accepted: 06/28/2024] [Indexed: 08/16/2024]
Abstract
Tissue-resident memory T (TRM) cells positively correlate with cancer survival, but the anti-tumor mechanisms underlying this relationship are not understood. This review reconciles these observations, summarizing concepts of T cell immunosurveillance, fundamental TRM cell biology, and clinical observations on the role of TRM cells in cancer and immunotherapy outcomes. We also discuss emerging strategies that utilize TRM-phenotype cells for patient diagnostics, staging, and therapy. Current challenges are highlighted, including a lack of standardized T cell nomenclature and our limited understanding of relationships between T cell markers and underlying tumor biology. Existing findings are integrated into a summary of the field while emphasizing opportunities for future research.
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Affiliation(s)
- Noah Veis Gavil
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Katarina Cheng
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - David Masopust
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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3
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Zhang J, Yao Z. Immune cell trafficking: a novel perspective on the gut-skin axis. Inflamm Regen 2024; 44:21. [PMID: 38654394 DOI: 10.1186/s41232-024-00334-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
Immune cell trafficking, an essential mechanism for maintaining immunological homeostasis and mounting effective responses to infections, operates under a stringent regulatory framework. Recent advances have shed light on the perturbation of cell migration patterns, highlighting how such disturbances can propagate inflammatory diseases from their origin to distal organs. This review collates and discusses current evidence that demonstrates atypical communication between the gut and skin, which are conventionally viewed as distinct immunological spheres, in the milieu of inflammation. We focus on the aberrant, reciprocal translocation of immune cells along the gut-skin axis as a pivotal factor linking intestinal and dermatological inflammatory conditions. Recognizing that the translation of these findings into clinical practices is nascent, we suggest that therapeutic strategies aimed at modulating the axis may offer substantial benefits in mitigating the widespread impact of inflammatory diseases.
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Affiliation(s)
- Jiayan Zhang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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4
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Ghahramanipour Z, Alipour S, Masoumi J, Rostamlou A, Hatami-Sadr A, Heris JA, Naseri B, Jafarlou M, Baradaran B. Regulation of Dendritic Cell Functions by Vitamins as Promising Therapeutic Strategy for Immune System Disorders. Adv Biol (Weinh) 2023; 7:e2300142. [PMID: 37423961 DOI: 10.1002/adbi.202300142] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/14/2023] [Indexed: 07/11/2023]
Abstract
A functional immune system is crucial for a healthy life, protecting from infections, tumors, or autoimmune disorders; these are accomplished by the interaction between various immune cells. Nourishment, particularly micronutrients, are very important components in the immune system balance, therefore this review emphasizes the vitamins (D, E, A, C) and Dendritic cells' subsets due to vitamins' roles in immune processes, especially on dendritic cells' functions, maturation, and cytokine production. Current studies reveal significant benefits related to vitamins, including vitamin E, which can contribute to the control of dendritic cells' function and maturation. Furthermore, vitamin D plays an immunoregulatory and anti-inflammatory role in the immune system. Metabolite of vitamin A which is called retinoic acid leads to T cells' differentiation to T helper 1 or T helper 17, so low levels of this vitamin exacerbate the menace of infectious diseases, and vitamin C has anti-oxidant effects on dendritic cells and modulate their activation and differentiation program. Additionally, the correlation between the amount of vitamin and the occurrence or progression of allergic diseases and autoimmunity disorders is discussed according to the results of previous studies.
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Affiliation(s)
- Zahra Ghahramanipour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
| | - Shiva Alipour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, 5165665931, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
| | - Arman Rostamlou
- Department of Medical Biology, Faculty of Medicine, University of EGE, Izmir, 35040, Turkey
| | | | - Javad Ahmadian Heris
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
| | - Mahdi Jafarlou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166616471, Iran
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5
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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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6
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Bang YJ. Vitamin A: a key coordinator of host-microbe interactions in the intestine. BMB Rep 2023; 56:133-139. [PMID: 36751944 PMCID: PMC10068342 DOI: 10.5483/bmbrep.2023-0005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/25/2023] [Accepted: 02/06/2023] [Indexed: 09/29/2023] Open
Abstract
The human intestine is home to a dense community of microbiota that plays a key role in human health and disease. Nutrients are essential regulators of both host and microbial physiology and function as key coordinators of host-microbe interactions. Therefore, understanding the specific roles and underlying mechanisms of each nutrient in regulating the host-microbe interactions will be essential in developing new strategies for improving human health through microbiota and nutrient intervention. This review will give a basic overview of the role of vitamin A, an essential micronutrient, on human health, and highlight recent findings on the mechanisms by which it regulates the host-microbe interactions. [BMB Reports 2023; 56(3): 133-139].
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Affiliation(s)
- Ye-Ji Bang
- Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 03080, Korea
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea
- Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Korea
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7
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Bang YJ. Vitamin A: a key coordinator of host-microbe interactions in the intestine. BMB Rep 2023; 56:133-139. [PMID: 36751944 PMCID: PMC10068342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/25/2023] [Accepted: 02/06/2023] [Indexed: 02/09/2023] Open
Abstract
The human intestine is home to a dense community of microbiota that plays a key role in human health and disease. Nutrients are essential regulators of both host and microbial physiology and function as key coordinators of host-microbe interactions. Therefore, understanding the specific roles and underlying mechanisms of each nutrient in regulating the host-microbe interactions will be essential in developing new strategies for improving human health through microbiota and nutrient intervention. This review will give a basic overview of the role of vitamin A, an essential micronutrient, on human health, and highlight recent findings on the mechanisms by which it regulates the host-microbe interactions. [BMB Reports 2023; 56(3): 133-139].
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Affiliation(s)
- Ye-Ji Bang
- Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 03080, Korea
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea
- Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Korea
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8
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Zagorulya M, Yim L, Morgan DM, Edwards A, Torres-Mejia E, Momin N, McCreery CV, Zamora IL, Horton BL, Fox JG, Wittrup KD, Love JC, Spranger S. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 2023; 56:386-405.e10. [PMID: 36736322 PMCID: PMC10880816 DOI: 10.1016/j.immuni.2023.01.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/27/2022] [Accepted: 01/11/2023] [Indexed: 02/05/2023]
Abstract
Local environmental factors influence CD8+ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8+ T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8+/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.
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Affiliation(s)
- Maria Zagorulya
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA
| | - Leon Yim
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Duncan M Morgan
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA
| | - Austin Edwards
- Biological Imaging Development CoLab, UCSF, San Francisco, CA 94143, USA
| | - Elen Torres-Mejia
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Noor Momin
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Chloe V McCreery
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Izabella L Zamora
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA
| | - Brendan L Horton
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - James G Fox
- Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Division of Comparative Medicine, MIT, Cambridge, MA 02139, USA
| | - K Dane Wittrup
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - J Christopher Love
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
| | - Stefani Spranger
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
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9
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Carlsen H, Ebihara K, Kuwata NH, Kuwata K, Aydemir G, Rühl R, Blomhoff R. A transgenic reporter mouse model for in vivo assessment of retinoic acid receptor transcriptional activation. INT J VITAM NUTR RES 2023; 93:29-41. [PMID: 33928787 DOI: 10.1024/0300-9831/a000705] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background: Vitamin A is essential for a wide range of life processes throughout embryogenesis to adult life. With the aim of developing an in vivo model to monitor retinoic acid receptor (RAR) transactivation real-time in intact animals, we generated transgenic mice carrying a luciferase (luc) reporter gene under the control of retinoic acid response elements (RAREs) consisting of three copies of a direct repeat with five spacing nucleotides (DR5). Methods: Transgenic mice carrying a RARE dependent luciferase reporter flanked with insulator sequence were generated by pronuclear injection. RARE dependent luciferase activity was detected by in vivo imaging or in tissue extracts following manipulations with RAR/retinoid X receptor (RXR) agonists, RAR antagonists or in vitamin A deficient mice. Results: We found a strong induction of luciferase activity in a time and dose dependent manner by retinoic acid as well as RAR agonists, but not by the RXR agonist (using n=4-6 per group; 94 mice). In addition, luciferase activity was strongly reduced in vitamin A-deficient mice (n=6-9; 30 mice). These observations confirm that luciferase activity was controlled by RAR activation in the RARE-luc mouse. Luciferase activity was detectable in various organs, with high activity especially in brain and testis, indicating strong retinoid signalling in these tissues. Conclusion: The RARE-luc transgenic mice, which enabled real-time in vivo assessment of RAR activation, will be useful in understanding the normal physiology of vitamin A, the role of retinoid signalling in pathologies as well as to evaluate pharmacological ligands for RARs.
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Affiliation(s)
- Harald Carlsen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.,Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
| | - Kanae Ebihara
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Nobuyo H Kuwata
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Kazuhisa Kuwata
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Gamze Aydemir
- Laboratory of Nutritional Bioactivation and Bioanalysis, Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
| | - Ralph Rühl
- Laboratory of Nutritional Bioactivation and Bioanalysis, Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.,Paprika Bioanalytics BT, Debrecen, Hungary
| | - Rune Blomhoff
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.,Department of Clinical Service, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
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10
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Zagorulya M, Spranger S. Once upon a prime: DCs shape cancer immunity. Trends Cancer 2023; 9:172-184. [PMID: 36357313 PMCID: PMC10827483 DOI: 10.1016/j.trecan.2022.10.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/05/2022] [Accepted: 10/12/2022] [Indexed: 11/09/2022]
Abstract
Cytotoxic CD8+ T cells are potent killers of diseased cells, but their functional capacity is often compromised in cancer. The quality of antitumor T cell immunity is determined during T cell priming in the lymph node and further influenced by the local microenvironment of the tumor. Increasing evidence indicates that dendritic cells (DCs) have the capacity to precisely regulate the functional quality of antitumor T cell responses in both locations. In this review, we discuss recent advances in our understanding of how distinct DC-derived signals influence CD8+ T cell differentiation and antitumor functions. Insight into the mechanisms of DC-mediated regulation of antitumor immunity could inspire the development of improved approaches to prevent and reverse T cell dysfunction in cancer.
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Affiliation(s)
- Maria Zagorulya
- Department of Biology, MIT, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Stefani Spranger
- Department of Biology, MIT, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Ludwig Center at MIT's Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
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11
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Hilt ZT, Charles W, Cheng KE, Tabilas C, Steinhilber M, Wesnak SP, Smith NL, Schaffer CB, Rudd BD. Cutting Edge: CCR9 Promotes CD8+ T Cell Recruitment to the Brain during Congenital Cytomegalovirus Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:2281-2286. [PMID: 36469843 PMCID: PMC9886274 DOI: 10.4049/jimmunol.2200578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/20/2022] [Indexed: 01/04/2023]
Abstract
CD8+ T lymphocytes infiltrate the brain during congenital CMV infection and promote viral clearance. However, the mechanisms by which CD8+ T cells are recruited to the brain remain unclear. Using a mouse model of congenital CMV, we found a gut-homing chemokine receptor (CCR9) was preferentially expressed in CD8+ T cells localized in the brain postinfection. In the absence of CCR9 or CCL25 (CCR9's ligand) expression, CD8+ T cells failed to migrate to key sites of infection in the brain and protect the host from severe forms of disease. Interestingly, we found that expression of CCR9 on CD8+ T cells was also responsible for spatial temporal positioning of T cells in the brain. Collectively, our data demonstrate that the CMV-infected brain uses a similar mechanism for CD8+ T cell homing as the small intestine.
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Affiliation(s)
- Zachary T. Hilt
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Wisler Charles
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Katarina E. Cheng
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Cybelle Tabilas
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Megan Steinhilber
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Samantha P. Wesnak
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Norah L. Smith
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Chris B. Schaffer
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Brian D. Rudd
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
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12
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Sterling KG, Dodd GK, Alhamdi S, Asimenios PG, Dagda RK, De Meirleir KL, Hudig D, Lombardi VC. Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease. Int J Mol Sci 2022; 23:13328. [PMID: 36362150 PMCID: PMC9655506 DOI: 10.3390/ijms232113328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer's disease, Parkinson's disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.
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Affiliation(s)
| | - Griffin Kutler Dodd
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Shatha Alhamdi
- Clinical Immunology and Allergy Division, Department of Pediatrics, King Abdullah Specialist Children’s Hospital, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia
| | | | - Ruben K. Dagda
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | | | - Dorothy Hudig
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Vincent C. Lombardi
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
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13
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Cheng L, Becattini S. Intestinal CD8 + tissue-resident memory T cells: From generation to function. Eur J Immunol 2022; 52:1547-1560. [PMID: 35985020 PMCID: PMC9804592 DOI: 10.1002/eji.202149759] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/21/2022] [Accepted: 08/10/2022] [Indexed: 01/05/2023]
Abstract
Tissue-resident memory T cells (Trm), and particularly the CD8+ subset, have been shown to play a pivotal role in protection against infections and tumors. Studies in animal models and human tissues have highlighted that, while a core functional program is shared by Trm at all anatomical sites, distinct tissues imprint unique features through specific molecular cues. The intestinal tissue is often the target of pathogens for local proliferation and penetration into the host systemic circulation, as well as a prominent site of tumorigenesis. Therefore, promoting the formation of Trm at this location is an appealing therapeutic option. The various segments composing the gastrointestinal tract present distinctive histological and functional characteristics, which may reflect on the imprinting of unique functional features in the respective Trm populations. What these features are, and whether they can effectively be harnessed to promote local and systemic immunity, is still under investigation. Here, we review how Trm are generated and maintained in distinct intestinal niches, analyzing the required molecular signals and the models utilized to uncover them. We also discuss evidence for a protective role of Trm against infectious agents and tumors. Finally, we integrate the knowledge obtained from animal models with that gathered from human studies.
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Affiliation(s)
- Liqing Cheng
- Department of Pathology and Immunology, Faculty of MedicineUniversity of GenevaGenevaSwitzerland,Geneva Centre for Inflammation Research, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Simone Becattini
- Department of Pathology and Immunology, Faculty of MedicineUniversity of GenevaGenevaSwitzerland,Geneva Centre for Inflammation Research, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
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14
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Bi G, Liang J, Bian Y, Shan G, Besskaya V, Wang Q, Zhan C. The immunomodulatory role of all-trans retinoic acid in tumor microenvironment. Clin Exp Med 2022:10.1007/s10238-022-00860-x. [PMID: 35829844 DOI: 10.1007/s10238-022-00860-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/28/2022] [Indexed: 12/19/2022]
Abstract
Retinoids are essential nutrients for human beings. Among them, all-trans retinoic acid (ATRA), considered one of the most active metabolites, plays important roles in multiple biological processes. ATRA regulates the transcription of target genes by interacting with nuclear receptors bonded to retinoic acid response elements (RAREs). Besides its differentiation-inducing effect in the treatment of acute promyelocytic leukemia and some solid tumor types, its immunoregulatory role in tumor microenvironment (TME) has attracted considerable attention. ATRA not only substantially abrogates the immunosuppressive effect of tumor-infiltrating myeloid-derived suppressor cells but also activates the anti-tumor effect of CD8 + T cells. Notably, the combination of ATRA with other therapeutic approaches, including immune checkpoint inhibitors (ICIs), tumor vaccines, and chemotherapy, has been extensively investigated in a variety of tumor models and clinical trials. In this review, we summarize the current understanding of the role of ATRA in cancer immunology and immunotherapy, dissect the underlying mechanisms of ATRA-mediated activation or differentiation of different types of immune cells, and explore the potential clinical significance of ATRA-based cancer therapy.
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Affiliation(s)
- Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Yunyi Bian
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Valeria Besskaya
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China.
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15
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IL-36 cytokines imprint a colitogenic phenotype on CD4 + T helper cells. Mucosal Immunol 2022; 15:491-503. [PMID: 35177818 PMCID: PMC9038530 DOI: 10.1038/s41385-022-00488-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 12/20/2021] [Accepted: 01/15/2022] [Indexed: 02/04/2023]
Abstract
IL-36 cytokines are emerging as potent orchestrators of intestinal inflammation and are being implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the mechanisms through which these cytokines mediate these effects remain to be fully uncovered. Here, we report specifically elevated expression of IL-36α, and not IL-36β or IL-36γ in the serum of newly diagnosed, treatment naïve, paediatric IBD patients and identify T cells as primary cellular mediators of IL-36 responses in the inflamed gut. IL-36R expression on CD4+ T cells was found to promote intestinal pathology in a murine model of colitis. Consistent with these effects, IL-36R can act as a potent instructor of CD4+ T cell differentiation in vivo, enhancing Th1 responses, while inhibiting the generation of Tregs. In addition, loss of IL-36 responsiveness significantly reduced the migration of pathogenic CD4+ T cells towards intestinal tissues and IL-36 was found to act, uniquely among IL-1 family members, to induce the expression of gut homing receptors in proinflammatory murine and human CD4+ T cells. These data reveal an important role for IL-36 cytokines in driving the colitogenic potential of CD4+ T cells and identify a new mechanism through which they may contribute to disease pathogenesis.
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16
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Zenewicz LA. IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology. Front Immunol 2021; 12:766586. [PMID: 34868019 PMCID: PMC8634938 DOI: 10.3389/fimmu.2021.766586] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/25/2021] [Indexed: 01/21/2023] Open
Abstract
Cytokines are powerful mediators of inflammation. Consequently, their potency is regulated in many ways to protect the host. Several cytokines, including IL-22, have coordinating binding proteins or soluble receptors that bind to the cytokine, block the interaction with the cellular receptor, and thus prevent cellular signaling. IL-22 is a critical cytokine in the modulation of tissue responses during inflammation and is highly upregulated in many chronic inflammatory disease patients, including those with psoriasis, rheumatoid arthritis, and inflammatory bowel disease (IBD). In healthy individuals, low levels of IL-22 are secreted by immune cells, mainly in the gastrointestinal (GI) tract. However, much of this IL-22 is likely not biologically active due to the high levels of IL-22 binding protein (IL-22BP) produced by intestinal dendritic cells (DCs). IL-22BP is a soluble receptor homolog that binds to IL-22 with greater affinity than the membrane spanning receptor. Much is known regarding the regulation and function of IL-22 in health and disease. However, less is known about IL-22BP. In this review, we will focus on IL-22BP, including its regulation, role in IL-22 biology and inflammation, and promise as a therapeutic. IL-22 can be protective or pathogenic, depending on the context of inflammation. IL-22BP also has divergent roles. Ongoing and forthcoming studies will expand our knowledge of IL-22BP and IL-22 biology, and suggest that IL-22BP holds promise as a way to regulate IL-22 biology in patients with chronic inflammatory disease.
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Affiliation(s)
- Lauren A. Zenewicz
- Department of Microbiology and Immunology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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17
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Bos AV, Erkelens MN, Koenders STA, van der Stelt M, van Egmond M, Mebius RE. Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells. Front Immunol 2021; 12:671283. [PMID: 34305901 PMCID: PMC8298001 DOI: 10.3389/fimmu.2021.671283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/02/2021] [Indexed: 01/24/2023] Open
Abstract
The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.
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Affiliation(s)
- Amelie V Bos
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
| | - Martje N Erkelens
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
| | - Sebastiaan T A Koenders
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands
| | - Marjolein van Egmond
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands.,Department of Surgery, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
| | - Reina E Mebius
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
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18
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Joeris T, Gomez-Casado C, Holmkvist P, Tavernier SJ, Silva-Sanchez A, Klotz L, Randall TD, Mowat AM, Kotarsky K, Malissen B, Agace WW. Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3 +CD8 + T regs. Sci Immunol 2021; 6:6/60/eabd3774. [PMID: 34088744 DOI: 10.1126/sciimmunol.abd3774] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 01/25/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
Although CD8+ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and suppressive function of FoxP3+CD8+ T cells. FoxP3+CD8+ Treg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1-derived PD-L1, TGFβ, and retinoic acid contributed to the generation of gut-tropic CCR9+CD103+FoxP3+CD8+ Tregs Last, CD103-deficient CD8+ T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3+CD8+ Treg function. Our results describe a role for FoxP3+CD8+ Tregs in cross-tolerance in the intestine for which development requires intestinal cDC1.
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Affiliation(s)
- Thorsten Joeris
- Mucosal Immunology Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, Kgs. Lyngby 2800, Denmark, Denmark.,Immunology Section, Lund University, Lund 221 84, Sweden
| | | | | | - Simon J Tavernier
- Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent 9000, Belgium.,VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, 9000 Ghent, Belgium
| | - Aaron Silva-Sanchez
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Luisa Klotz
- University Hospital Münster, Department of Neurology with Institute of Translational Neurology, Münster 48149, Germany
| | - Troy D Randall
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Allan M Mowat
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland
| | - Knut Kotarsky
- Immunology Section, Lund University, Lund 221 84, Sweden
| | - Bernard Malissen
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS, Marseille, France
| | - William W Agace
- Mucosal Immunology Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, Kgs. Lyngby 2800, Denmark, Denmark. .,Immunology Section, Lund University, Lund 221 84, Sweden
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19
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Satomi S, Khanum S, Miller P, Suzuki S, Suganuma H, Heiser A, Gupta SK. Short Communication: Oral Administration of Heat-killed Lactobacillus brevis KB290 in Combination with Retinoic Acid Provides Protection against Influenza Virus Infection in Mice. Nutrients 2020; 12:nu12102925. [PMID: 32987850 PMCID: PMC7600661 DOI: 10.3390/nu12102925] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/16/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022] Open
Abstract
Influenza virus type A (IAV) is a seasonal acute respiratory disease virus with severe symptoms, and an effective preventive measure is required. Despite many reports describing the potentially protective effects of lactic acid bacteria, few studies have investigated the effects of nutritional supplement combinations. This study reports the effect of the combined intake of heat-killed Lactobacillus brevis KB290 (KB290) and vitamin A (VA) on mice challenged with a sublethal dose of IAV. For 2 weeks, five groups of mice were fed either placebo, KB290, VA, or a combination of KB290 and VA (KB290+VA). After subsequent IAV challenge, bodyweight and general health were monitored for up to 2 weeks. Viral titres were determined in the lungs of animal subgroups euthanised at days 3, 7, and 14 after IAV challenge. A significant loss was observed in the bodyweights of IAV-infected animals from day 1 post-IAV challenge, whereas the mice fed KB290+VA did not lose any weight after IAV infection, indicating successful protection from the infection. Additionally, mice in the KB290+VA group showed the highest reduction in lung viral titres. In conclusion, the combination of KB290 and VA could be a useful food supplement relevant for protection against seasonal influenza virus infection in humans.
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Affiliation(s)
- Shohei Satomi
- Department of Nature & Wellness Research, Innovation Division, KAGOME CO., LTD., 17 Nishitomiyama, Nasushiobara, Tochigi 329-2762, Japan; (S.S.); (H.S.)
- Correspondence: (S.S.); (S.K.G.); Tel.: +81-80-8132-3813 (S.S.); +64-06351-8697 (S.K.G.)
| | - Sofia Khanum
- AgResearch Ltd., Hopkirk Research Institute, Grasslands Research Centre, Private Bag 11008, Palmerston North 4442, New Zealand; (S.K.); (P.M.); (A.H.)
| | - Poppy Miller
- AgResearch Ltd., Hopkirk Research Institute, Grasslands Research Centre, Private Bag 11008, Palmerston North 4442, New Zealand; (S.K.); (P.M.); (A.H.)
| | - Shigenori Suzuki
- Department of Nature & Wellness Research, Innovation Division, KAGOME CO., LTD., 17 Nishitomiyama, Nasushiobara, Tochigi 329-2762, Japan; (S.S.); (H.S.)
| | - Hiroyuki Suganuma
- Department of Nature & Wellness Research, Innovation Division, KAGOME CO., LTD., 17 Nishitomiyama, Nasushiobara, Tochigi 329-2762, Japan; (S.S.); (H.S.)
| | - Axel Heiser
- AgResearch Ltd., Hopkirk Research Institute, Grasslands Research Centre, Private Bag 11008, Palmerston North 4442, New Zealand; (S.K.); (P.M.); (A.H.)
| | - Sandeep K Gupta
- AgResearch Ltd., Hopkirk Research Institute, Grasslands Research Centre, Private Bag 11008, Palmerston North 4442, New Zealand; (S.K.); (P.M.); (A.H.)
- Correspondence: (S.S.); (S.K.G.); Tel.: +81-80-8132-3813 (S.S.); +64-06351-8697 (S.K.G.)
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20
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Balmer ML, Ma EH, Thompson AJ, Epple R, Unterstab G, Lötscher J, Dehio P, Schürch CM, Warncke JD, Perrin G, Woischnig AK, Grählert J, Löliger J, Assmann N, Bantug GR, Schären OP, Khanna N, Egli A, Bubendorf L, Rentsch K, Hapfelmeier S, Jones RG, Hess C. Memory CD8 + T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection. Cell Metab 2020; 32:457-467.e5. [PMID: 32738204 DOI: 10.1016/j.cmet.2020.07.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 04/21/2020] [Accepted: 07/12/2020] [Indexed: 12/31/2022]
Abstract
Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type.
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Affiliation(s)
- Maria L Balmer
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
| | - Eric H Ma
- Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Physiology, McGill University, Montreal, QC, Canada
| | - Andrew J Thompson
- Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Raja Epple
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Gunhild Unterstab
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Jonas Lötscher
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Philippe Dehio
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Christian M Schürch
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA
| | - Jan D Warncke
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Gaëlle Perrin
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Anne-Kathrin Woischnig
- Department of Biomedicine, Laboratory of Infection Biology, University of Basel and University Hospital Basel, 4031 Basel, Switzerland
| | - Jasmin Grählert
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Jordan Löliger
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Nadine Assmann
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Glenn R Bantug
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland
| | - Olivier P Schären
- Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland
| | - Nina Khanna
- Department of Biomedicine, Laboratory of Infection Biology, University of Basel and University Hospital Basel, 4031 Basel, Switzerland
| | - Adrian Egli
- Clinical Microbiology, University Hospital Basel, 4031 Basel, Switzerland; Applied Microbiology Research, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Lukas Bubendorf
- Institute for Pathology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | - Katharina Rentsch
- Department of Laboratory Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | | | - Russell G Jones
- Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Physiology, McGill University, Montreal, QC, Canada
| | - Christoph Hess
- Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
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21
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Barber-Axthelm IM, Kent SJ, Juno JA. Understanding the Role of Mucosal-Associated Invariant T-Cells in Non-human Primate Models of HIV Infection. Front Immunol 2020; 11:2038. [PMID: 33013862 PMCID: PMC7461791 DOI: 10.3389/fimmu.2020.02038] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 07/27/2020] [Indexed: 12/19/2022] Open
Abstract
Chronic HIV infection causes systemic immune activation and dysregulation, resulting in the impairment of most T-cell subsets including MAIT cells. Multiple human cohort studies demonstrate MAIT cells are selectively depleted in the peripheral blood and lymphoid tissues during HIV infection, with incomplete restoration during suppressive antiretroviral therapy. Because MAIT cells play an important role in mucosal defense against a wide array of pathogens, fully reconstituting the MAIT cell compartment in ART-treated populations could improve immunity against co-infections. Non-human primates (NHPs) are a valuable, well-described animal model for HIV infection in humans. NHPs also maintain MAIT cell frequencies more comparable to humans, compared to other common animal models, and provide a unique opportunity to study MAIT cells in the circulation and mucosal tissues in a longitudinal manner. Only recently, however, have NHP MAIT cells been thoroughly characterized using macaque-specific MR1 tetramer reagents. Here we review the similarities and differences between MAIT cells in humans and NHPs as well as the impact of SIV/SHIV infection on MAIT cells and the potential implications for future research.
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Affiliation(s)
- Isaac M Barber-Axthelm
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
| | - Stephen J Kent
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.,Department of Infectious Diseases, Melbourne Sexual Health Centre, Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC, Australia.,ARC Centre for Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Melbourne, VIC, Australia
| | - Jennifer A Juno
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
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22
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Du Y, Xia Y, Zou Y, Hu Y, Fu J, Wu J, Gao XD, Ma G. Exploiting the Lymph-Node-Amplifying Effect for Potent Systemic and Gastrointestinal Immune Responses via Polymer/Lipid Nanoparticles. ACS NANO 2019; 13:13809-13817. [PMID: 31621292 DOI: 10.1021/acsnano.9b04071] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Parenteral vaccinations are not able to elicit effective systemic and gastrointestinal immune protection simultaneously because the lymphocytes are typically restricted to primed tissues. Although all-trans retinoic acid (atRA) was reported to trigger the gut-homing of immunocytes, the bioavailability and systemic immune responses remain limited for use in robust enteric vaccinations. Here, we show that co-delivery of atRA, CpG oligodeoxynucleotides (CpG), and antigens via engineered polymer/lipid nanoparticles (PLNPs) could exploit the amplifying function of draining lymph nodes (DLNs) for potent gut tropism and immune activations. After intramuscular injection, forming an immune-potentiated environment at the injection site, the PLNPs induced the designated transfer of primed dendritic cells (DCs) to the DLNs instead of the gastrointestinal tissues. Within the DLNs, the immune-potentiated environment markedly amplified the antigen presentation and homing receptor switch among immunocytes, which simultaneously stimulated the preferential dissipation of activated lymphocytes in the peripheral and gastrointestinal tissues, that is, exerted a DLN-amplifying effect. Compared with current atRA-containing formulations, the PLNPs not only boosted potent IgG secretions and T cell activations in the peripheral tissue but also provoked robust T cell homing and antigen-specific IgA levels in the gastrointestinal tracts in both ovalbumin and EV71 vaccinations. These data indicate that exploiting DLN amplification can stimulate potent systemic and gastrointestinal responses for more efficient enteric vaccinations.
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Affiliation(s)
- Yiqun Du
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology , Jiangnan University , Wuxi 214122 , P.R. China
| | - Yufei Xia
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
- University of Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Yongjuan Zou
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
- University of Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Yuning Hu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
- University of Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Jiaqi Fu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Jie Wu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
- PLA Key Laboratory of Biopharmaceutical Production and Formulation Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Xiao-Dong Gao
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology , Jiangnan University , Wuxi 214122 , P.R. China
| | - Guanghui Ma
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
- University of Chinese Academy of Sciences , Beijing 100190 , P.R. China
- PLA Key Laboratory of Biopharmaceutical Production and Formulation Engineering, Institute of Process Engineering , Chinese Academy of Sciences , Beijing 100190 , P.R. China
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23
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Juno JA, Wragg KM, Amarasena T, Meehan BS, Mak JYW, Liu L, Fairlie DP, McCluskey J, Eckle SBG, Kent SJ. MAIT Cells Upregulate α4β7 in Response to Acute Simian Immunodeficiency Virus/Simian HIV Infection but Are Resistant to Peripheral Depletion in Pigtail Macaques. THE JOURNAL OF IMMUNOLOGY 2019; 202:2105-2120. [PMID: 30777923 DOI: 10.4049/jimmunol.1801405] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 01/23/2019] [Indexed: 11/19/2022]
Abstract
Mucosal-associated invariant T (MAIT) cells are nonconventional T lymphocytes that recognize bacterial metabolites presented by MR1. Whereas gut bacterial translocation and the loss/dysfunction of peripheral MAIT cells in HIV infection is well described, MAIT cells in nonhuman primate models are poorly characterized. We generated a pigtail macaque (PTM)-specific MR1 tetramer and characterized MAIT cells in serial samples from naive and SIV- or simian HIV-infected PTM. Although PTM MAIT cells generally resemble the phenotype and transcriptional profile of human MAIT cells, they exhibited uniquely low expression of the gut-homing marker α4β7 and were not enriched at the gut mucosa. PTM MAIT cells responded to SIV/simian HIV infection by proliferating and upregulating α4β7, coinciding with increased MAIT cell frequency in the rectum. By 36 wk of infection, PTM MAIT cells were activated and exhibited a loss of Tbet expression but were not depleted as in HIV infection. Our data suggest the following: 1) MAIT cell activation and exhaustion is uncoupled from the hallmark depletion of MAIT cells during HIV infection; and 2) the lack of PTM MAIT cell enrichment at the gut mucosa may prevent depletion during chronic infection, providing a model to assess potential immunotherapeutic approaches to modify MAIT cell trafficking during HIV infection.
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Affiliation(s)
- Jennifer A Juno
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia;
| | - Kathleen M Wragg
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia
| | - Thakshila Amarasena
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia
| | - Bronwyn S Meehan
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia
| | - Jeffrey Y W Mak
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Queensland 4072, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Queensland 4072, Australia
| | - Ligong Liu
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Queensland 4072, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Queensland 4072, Australia
| | - David P Fairlie
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Queensland 4072, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Queensland 4072, Australia
| | - James McCluskey
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia
| | - Sidonia B G Eckle
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia
| | - Stephen J Kent
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria 3000, Australia.,Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Health, Central Clinical School, Monash University, Victoria 3053, Australia; and.,Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Victoria 3000, Australia
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24
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Li P, Wang J, Cao M, Deng Q, Jiang S, Wu MX, Lu L. Topical Application of a Vitamin A Derivative and Its Combination With Non-ablative Fractional Laser Potentiates Cutaneous Influenza Vaccination. Front Microbiol 2018; 9:2570. [PMID: 30425691 PMCID: PMC6218415 DOI: 10.3389/fmicb.2018.02570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/09/2018] [Indexed: 12/21/2022] Open
Abstract
Skin contains a large number of antigen presenting cells, making intradermal (ID) injection one of the most effective ways for vaccine administration. However, although current adjuvants may cause severe local reactions and inflammations in the skin, no adjuvant has been approved for ID vaccination so far. Here, we report that topical application of all-trans retinoic acid (ATRA), a vitamin A derivative produced in the human body, augmented cutaneous influenza vaccination. The adjuvant effects were evaluated in a murine vaccination/challenge model by using A/California/07/2009 pandemic vaccine (09V) or a seasonal influenza vaccine (SIV). ATRA drove a Th2-biased immune response, as demonstrated by profoundly elevated IgG1 titer rather than IgG2 titer. Combining ATRA with a non-ablative fractional laser (NAFL), which represents a new category of vaccine adjuvant utilizing physical stimuli to induce self-immune stimulators, further enhanced the efficacy of influenza vaccines with a more balanced Th1/Th2 immune response. The dual adjuvant strengthened cross-reactive immune responses against both homogenous and heterogeneous influenza viral strains. Analysis of gene expression profile showed that ATRA/NAFL stimulated upregulation of cytosolic nucleic acid sensors and their downstream factors, leading to a synergistic elevation of type I interferon expression. Consistent with this finding, knocking out IRF3 or IRF7, two key downstream regulatory factors in most nucleic acid sensing pathways, resulted in a significant decrease in the adjuvant effect of ATRA/NAFL. Thus, our study demonstrates that the self molecule ATRA could boost cutaneous influenza vaccination either alone or ideally in combination with NAFL.
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Affiliation(s)
- Peiyu Li
- Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA, United States
- Department of Infectious Diseases and the Key Lab of Endogenous Infection, Shenzhen Nanshan People’s Hospital, Guangdong Medical University, Shenzhen, China
| | - Ji Wang
- Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA, United States
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
| | - Miao Cao
- Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qiwen Deng
- Department of Infectious Diseases and the Key Lab of Endogenous Infection, Shenzhen Nanshan People’s Hospital, Guangdong Medical University, Shenzhen, China
| | - Shibo Jiang
- Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, United States
| | - Mei X. Wu
- Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA, United States
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States
| | - Lu Lu
- Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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25
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Weiberg D, Basic M, Smoczek M, Bode U, Bornemann M, Buettner M. Participation of the spleen in the IgA immune response in the gut. PLoS One 2018; 13:e0205247. [PMID: 30286198 PMCID: PMC6171922 DOI: 10.1371/journal.pone.0205247] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 09/23/2018] [Indexed: 11/18/2022] Open
Abstract
The role of the spleen in the induction of an immune response to orally administered antigens is still under discussion. Although it is well known that after oral antigen administration specific germinal centres are not only formed in the Peyers patches (PP) and the mesenteric lymph nodes (mLN) but also in the spleen, there is still a lack of functional data showing a direct involvement of splenic B cells in an IgA immune response in the gut. In addition, after removal of mLN a high level of IgA+ B cells was observed in the gut. Therefore, in this study we analysed the role of the spleen in the induction of IgA+ B cells in the gut after mice were orally challenged with antigens. Here we have shown that antigen specific splenic IgM+ B cells after in vitro antigen stimulation as well as oral immunisation of donor mice were able to migrate into the gut of recipient mice, where they predominantly switch to IgA+ plasma cells. Furthermore, stimulation of recipient mice by orally administered antigens enhanced the migration of the splenic B cells into the gut as well as their switch to IgA+ plasma cells. Removal of the mLN led to a higher activation level of the splenic B cells. Altogether, our results imply that splenic IgM+ B cells migrate in the intestinal lamina propria, where they differentiate into IgA+ plasma cells and subsequently proliferate. In conclusion, we demonstrated that the spleen plays a major role in the gut immune response serving as a reservoir of immune cells that migrate to the site of antigen entrance.
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Affiliation(s)
- Desiree Weiberg
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Margarethe Smoczek
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Ulrike Bode
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Melanie Bornemann
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Manuela Buettner
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
- * E-mail:
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26
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Huang Z, Liu Y, Qi G, Brand D, Zheng SG. Role of Vitamin A in the Immune System. J Clin Med 2018; 7:E258. [PMID: 30200565 PMCID: PMC6162863 DOI: 10.3390/jcm7090258] [Citation(s) in RCA: 291] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 08/23/2018] [Accepted: 08/31/2018] [Indexed: 12/20/2022] Open
Abstract
Vitamin A (VitA) is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. VitA is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. VitA is involved in the development of the immune system and plays regulatory roles in cellular immune responses and humoral immune processes. VitA has demonstrated a therapeutic effect in the treatment of various infectious diseases. To better understand the relationship between nutrition and the immune system, the authors review recent literature about VitA in immunity research and briefly introduce the clinical application of VitA in the treatment of several infectious diseases.
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Affiliation(s)
- Zhiyi Huang
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, Guangxi, China.
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, Guangxi, China.
| | - Yu Liu
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, Guangxi, China.
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, Guangxi, China.
| | - Guangying Qi
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, Guangxi, China.
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, Guangxi, China.
| | - David Brand
- Research Service, VA Medical Center, Memphis, TN 38104, USA.
| | - Song Guo Zheng
- Department of Medicine, Division of Rheumatology, Milton S. Hershey Medical Center at Penn State University, Hershey, PA 17033, USA.
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27
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Corbo C, Cromer WE, Molinaro R, Toledano Furman NE, Hartman KA, De Rosa E, Boada C, Wang X, Zawieja DC, Agostini M, Salvatore F, Abraham BP, Tasciotti E. Engineered biomimetic nanovesicles show intrinsic anti-inflammatory properties for the treatment of inflammatory bowel diseases. NANOSCALE 2017; 9:14581-14591. [PMID: 28932838 DOI: 10.1039/c7nr04734g] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal (GI) tract. Currently, it is treated with immunosuppressant or biologics that often induce severe adverse effects. Thus, there is an urgent clinical need for more specific treatments. To provide a valid therapeutic tool for IBD therapy, in this work we developed biomimetic nanovesicles by manipulating leukocyte membranes to exploit mechanisms of T-cell recruitment during inflammation. A subset of T-lymphocytes participates in homing to inflamed tissue in the gastrointestinal tract by overexpressing the α4β7 integrin, which is responsible for binding to its receptor on the endothelial membrane, the mucosal addressin cell adhesion molecule 1. Based on this principle, we engineered biomimetic vesicles, referred to as specialized leukosomes (SLKs), which are leukocyte-like carriers 'doped' with the α4β7 integrin over-induced in purified immune cells. We tested SLKs in an in vivo murine model of IBD induced by treatment with dextran sulfate sodium. Notably, treatment of IBD mice with SLKs allowed us to observe a reduction of inflammation (favorable modulation of both pro- and anti-inflammatory genes, as well as reduction of immune cells infiltration into the colon tissue), and a consequent enhanced intestinal repair (low epithelial damage). In this study, we demonstrate that biological-derived nanoparticles can be used not only as naturally targeted drug delivery systems, but also as nano-therapeutics endowed with intrinsic anti-inflammatory properties.
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Affiliation(s)
- Claudia Corbo
- Center for Biomimetic Medicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77002, USA.
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28
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Furlong S, Power Coombs MR, Hoskin DW. Thy-1 stimulation of mouse T cells induces a delayed T cell receptor-like signal that results in Ca2+‑independent cytotoxicity. Mol Med Rep 2017; 16:5683-5692. [PMID: 28849009 DOI: 10.3892/mmr.2017.7242] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 06/26/2017] [Indexed: 11/05/2022] Open
Abstract
Antibody-mediated crosslinking of Thy-1 [also known as cluster of differentiation (CD)90], results in a T cell receptor (TcR)‑like signal; however, the impact of Thy‑1 stimulation in comparison to TcR stimulation on T cell activation and effector function has yet to be fully elucidated. In the present study, the outcome of Thy‑1‑ and TcR‑induced stimulation of T cells was investigated in mice, using fragment crystalizable (Fc) receptor‑bound antibodies and costimulatory signals provided by syngeneic lipopolysaccharide‑matured bone marrow‑derived dendritic cells. Compared with TcR signaling, Thy‑1 signaling initiated a less robust proliferative response in T cells, as determined by tritiated‑thymidine incorporation. In addition, enzyme‑linked immunosorbent assays revealed that interleukin‑2 production was reduced, and the expression of CD25 and cyclin D3 was weaker in Thy‑1‑stimulated cells, as determined by western blotting; however, the expression of cyclin‑dependent kinase 6 was similar to that in TcR‑induced T cells. Furthermore, western blotting demonstrated that the phosphorylation of ζ-chain‑associated protein kinase 70 and extracellular signal‑regulated kinase 1/2 was delayed following Thy‑1 stimulation. DNA fragmentation assays revealed that cytotoxic effector function was also slower to develop in Thy‑1‑stimulated T cells, required more time to be effective and was largely Ca2+‑independent; these findings suggested that Fas ligand rather than granule‑associated perforin was involved in T cell effector function. In conclusion, the present results suggested that Thy‑1 signaling may contribute to the regulation of T cell homeostasis and the development of non‑specific T cell‑mediated cytotoxicity. However, further studies are required to elucidate the exact physiological roles of TcR‑like signals that result from Thy‑1 crosslinking and to investigate the molecular mechanisms that are involved.
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Affiliation(s)
- Suzanne Furlong
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | | | - David W Hoskin
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
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29
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Agace WW, McCoy KD. Regionalized Development and Maintenance of the Intestinal Adaptive Immune Landscape. Immunity 2017; 46:532-548. [PMID: 28423335 DOI: 10.1016/j.immuni.2017.04.004] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/03/2017] [Accepted: 04/04/2017] [Indexed: 12/14/2022]
Abstract
The intestinal immune system has the daunting task of protecting us from pathogenic insults while limiting inflammatory responses against the resident commensal microbiota and providing tolerance to food antigens. This role is particularly impressive when one considers the vast mucosal surface and changing landscape that the intestinal immune system must monitor. In this review, we highlight regional differences in the development and composition of the adaptive immune landscape of the intestine and the impact of local intrinsic and environmental factors that shape this process. To conclude, we review the evidence for a critical window of opportunity for early-life exposures that affect immune development and alter disease susceptibility later in life.
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Affiliation(s)
- William W Agace
- Division of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark (DTU), 2800 Kongens Lyngby, Denmark; Immunology Section, Department of Experimental Medical Science, Lund University, BMC D14, Sölvegatan 19, 221 84 Lund, Sweden.
| | - Kathy D McCoy
- Department of Physiology and Pharmacology and Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
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30
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Novel Insights into the Mechanisms of Gut Homing and Antiadhesion Therapies in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2017; 23:617-627. [PMID: 28296823 DOI: 10.1097/mib.0000000000001067] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Therapeutic compounds interfering with T cell trafficking are a new column of inflammatory bowel disease (IBD) treatment. Currently, the anti-α4β7 integrin antibody vedolizumab is successfully used in the clinic and further drugs are likely to follow. Despite these clinical advances, the precise mechanistic background of their action is only gradually elucidated and still a matter of intensive research. Only recently, advances made with the help of new in vivo models and human studies have contributed to shape our concept of T cell trafficking in IBD by deciphering some important and so far unanswered questions. At the same time, basic and clinical data have generated new issues to be addressed on the way toward a clear perception of trafficking mechanisms and toward elucidation of the action of compounds interfering with this process. In this review, we will give a comprehensive outline of all components of T cell trafficking in regard to IBD before discussing the current knowledge concerning targeted interference with integrins in this complex network. Moreover, we will summarize remaining ambiguity and give an outlook on potential future targets.
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31
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Shea-Donohue T, Qin B, Smith A. Parasites, nutrition, immune responses and biology of metabolic tissues. Parasite Immunol 2017; 39. [PMID: 28235148 DOI: 10.1111/pim.12422] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 02/21/2017] [Indexed: 02/06/2023]
Abstract
Nutritional immunology, immunometabolism and identification of novel immunotherapeutic targets are areas of active investigation in parasitology. There is a well-documented crosstalk among immune cells and cells in metabolically active tissues that is important for homeostasis. The numbers and function of these cells are altered by obesity leading to inflammation. A variety of helminths spend some part of their life cycle in the gastrointestinal tract and even entirely enteral nematode infections exert beneficial effects on glucose and lipid metabolism. The foundation of this review is the ability of enteric nematode infections to improve obesity-induced type 2 diabetes and the metabolic syndrome, which are significant health issues in developed areas. It considers the impact of nutrition and specific nutritional deficiencies, which are occur in both undeveloped and developed areas, on the host's ability mount a protective immune response against parasitic nematodes. There are a number of proposed mechanisms by which parasitic nematodes can impact metabolism including effects gastrointestinal hormones, altering epithelial function and changing the number and/or phenotype of immune cells in metabolic tissues. Nematodes can also exert their beneficial effects through Th2 cytokines that activate the transcription factor STAT6, which upregulates genes that regulate glucose and lipid metabolism.
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Affiliation(s)
- T Shea-Donohue
- Department of Radiation Oncology & Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - B Qin
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USA
| | - A Smith
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USA
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32
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Duurland CL, Brown CC, O'Shaughnessy RFL, Wedderburn LR. CD161 + Tconv and CD161 + Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire. Front Immunol 2017; 8:103. [PMID: 28321213 PMCID: PMC5337494 DOI: 10.3389/fimmu.2017.00103] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 01/20/2017] [Indexed: 12/20/2022] Open
Abstract
Human regulatory T cells (Treg) are important in immune regulation, but can also show plasticity in specific settings. CD161 is a lectin-like receptor and its expression identifies an effector-like Treg population. Here, we determined how CD161+ Treg relate to CD161+ conventional T cells (Tconv). Transcriptional profiling identified a shared transcriptional signature between CD161+ Tconv and CD161+ Treg, which is associated with T helper (Th)1 and Th17 cells, and tissue homing, including high expression of gut-homing receptors. Upon retinoic acid (RA) exposure, CD161+ T cells were more enriched for CCR9+ and integrin α4+β7+ cells than CD161- T cells. In addition, CD161+ Tconv and CD161+ Treg were enriched at the inflamed site in autoimmune arthritis, and both CD161+ and CD161- Treg from the inflamed site were suppressive in vitro. CD161+ T cells from the site of autoimmune arthritis showed a diminished gut-homing phenotype and blunted response to RA suggesting prior imprinting by RA in the gut or at peripheral sites rather than during synovial inflammation. TCRβ repertoires of CD161+ and CD161- Tconv and Treg from blood showed limited overlap whereas there was clear overlap between CD161+ and CD161- Tconv, and CD161+ and CD161- Treg from the inflamed site suggesting that the inflamed environment may alter CD161 levels, potentially contributing to disease pathogenesis.
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Affiliation(s)
- Chantal L Duurland
- Infection, Inflammation and Rheumatology Section, Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL) , London , UK
| | - Chrysothemis C Brown
- Infection, Inflammation and Rheumatology Section, Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL) , London , UK
| | - Ryan F L O'Shaughnessy
- Immunobiology Section, Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL) , London , UK
| | - Lucy R Wedderburn
- Infection, Inflammation and Rheumatology Section, Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK; Arthritis Research UK Centre for Adolescent Rheumatology, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK; UK National Institute for Health Research (NIHR) GOSH Biomedical Research Centre, London, UK
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33
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Bono MR, Tejon G, Flores-Santibañez F, Fernandez D, Rosemblatt M, Sauma D. Retinoic Acid as a Modulator of T Cell Immunity. Nutrients 2016; 8:E349. [PMID: 27304965 PMCID: PMC4924190 DOI: 10.3390/nu8060349] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 05/20/2016] [Accepted: 06/01/2016] [Indexed: 12/30/2022] Open
Abstract
Vitamin A, a generic designation for an array of organic molecules that includes retinal, retinol and retinoic acid, is an essential nutrient needed in a wide array of aspects including the proper functioning of the visual system, maintenance of cell function and differentiation, epithelial surface integrity, erythrocyte production, reproduction, and normal immune function. Vitamin A deficiency is one of the most common micronutrient deficiencies worldwide and is associated with defects in adaptive immunity. Reports from epidemiological studies, clinical trials and experimental studies have clearly demonstrated that vitamin A plays a central role in immunity and that its deficiency is the cause of broad immune alterations including decreased humoral and cellular responses, inadequate immune regulation, weak response to vaccines and poor lymphoid organ development. In this review, we will examine the role of vitamin A in immunity and focus on several aspects of T cell biology such as T helper cell differentiation, function and homing, as well as lymphoid organ development. Further, we will provide an overview of the effects of vitamin A deficiency in the adaptive immune responses and how retinoic acid, through its effect on T cells can fine-tune the balance between tolerance and immunity.
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Affiliation(s)
- Maria Rosa Bono
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Gabriela Tejon
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Felipe Flores-Santibañez
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Dominique Fernandez
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Mario Rosemblatt
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
- Fundacion Ciencia & Vida, Santiago 7780272, Chile.
- Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago 8370146, Chile.
| | - Daniela Sauma
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
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34
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IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis. Immunity 2016; 44:860-74. [DOI: 10.1016/j.immuni.2016.02.008] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 12/16/2015] [Accepted: 02/09/2016] [Indexed: 02/07/2023]
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35
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Wendt E, White GE, Ferry H, Huhn M, Greaves DR, Keshav S. Glucocorticoids Suppress CCR9-Mediated Chemotaxis, Calcium Flux, and Adhesion to MAdCAM-1 in Human T Cells. THE JOURNAL OF IMMUNOLOGY 2016; 196:3910-9. [PMID: 27016601 DOI: 10.4049/jimmunol.1500619] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 02/22/2016] [Indexed: 12/18/2022]
Abstract
CCR9 expressed on T lymphocytes mediates migration to the small intestine in response to a gradient of CCL25. CCL25-stimulated activation of α4β7 integrin promotes cell adherence to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed by vascular endothelial cells of the intestine, further mediating gut-specific homing. Inflammatory bowel disease is a chronic inflammatory condition that primarily affects the gastrointestinal tract and is characterized by leukocyte infiltration. Glucocorticoids (GCs) are widely used to treat inflammatory bowel disease but their effect on intestinal leukocyte homing is not well understood. We investigated the effect of GCs on the gut-specific chemokine receptor pair, CCR9 and CCL25. Using human peripheral blood-derived T lymphocytes enriched for CCR9 by cell sorting or culturing with all-trans retinoic acid, we measured chemotaxis, intracellular calcium flux, and α4β7-mediated cell adhesion to plate-bound MAdCAM-1. Dexamethasone (DEX), a specific GC receptor agonist, significantly reduced CCR9-mediated chemotaxis and adhesion to MAdCAM-1 without affecting CCR9 surface expression. In contrast, in the same cells, DEX increased CXCR4 surface expression and CXCL12-mediated signaling and downstream functions. The effects of DEX on human primary T cells were reversed by the GC receptor antagonist mifepristone. These results demonstrate that GCs suppress CCR9-mediated chemotaxis, intracellular calcium flux, and α4β7-mediated cell adhesion in vitro, and these effects could contribute to the efficacy of GCs in treating intestinal inflammation in vivo.
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Affiliation(s)
- Emily Wendt
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Gemma E White
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and
| | - Helen Ferry
- Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Michael Huhn
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - David R Greaves
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and
| | - Satish Keshav
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom;
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Houston SA, Cerovic V, Thomson C, Brewer J, Mowat AM, Milling S. The lymph nodes draining the small intestine and colon are anatomically separate and immunologically distinct. Mucosal Immunol 2016; 9:468-78. [PMID: 26329428 DOI: 10.1038/mi.2015.77] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 07/19/2015] [Indexed: 02/04/2023]
Abstract
Dendritic cells (DCs) in the small intestine (SI) and colon are fundamental to direct intestinal immune responses; they migrate to the mesenteric lymph nodes (MLNs) and prime T cells. We demonstrate anatomical segregation of lymphatic drainage from the intestine, specifically that DCs from the SI and colon migrate to different nodes within the MLN, here called the sMLN and cMLN. As a consequence, different frequencies of DC subsets observed in the SI and colon are reflected among the DCs in the sMLN and cMLN. Consistent with the SI's function in absorbing food, fed antigen is presented in the sMLN, but not in the cMLN. Furthermore, the levels of expression of CCR9 and α4β7 are increased on T cells in the sMLN compared with the cMLN. DCs from the cMLN and colon are unable to metabolize vitamin A to retinoic acid (RA); thus, DCs may contribute to the differential expression of tissue homing markers observed in the sMLN and cMLN. In summary, the sMLN and cMLN, and the DCs that migrate to these LNs are anatomically and immunologically separate. This segregation allows immune responses in the SI and colon to be controlled independently.
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Affiliation(s)
- S A Houston
- Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - V Cerovic
- Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - C Thomson
- Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - J Brewer
- Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - A M Mowat
- Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - S Milling
- Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
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Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells. Mediators Inflamm 2016; 2016:3104727. [PMID: 27034589 PMCID: PMC4789473 DOI: 10.1155/2016/3104727] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 02/02/2016] [Accepted: 02/08/2016] [Indexed: 12/25/2022] Open
Abstract
Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions.
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38
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Tian Y, Cox MA, Kahan SM, Ingram JT, Bakshi RK, Zajac AJ. A Context-Dependent Role for IL-21 in Modulating the Differentiation, Distribution, and Abundance of Effector and Memory CD8 T Cell Subsets. THE JOURNAL OF IMMUNOLOGY 2016; 196:2153-66. [PMID: 26826252 DOI: 10.4049/jimmunol.1401236] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 12/31/2015] [Indexed: 12/21/2022]
Abstract
The activation of naive CD8 T cells typically results in the formation of effector cells (TE) as well as phenotypically distinct memory cells that are retained over time. Memory CD8 T cells can be further subdivided into central memory, effector memory (TEM), and tissue-resident memory (TRM) subsets, which cooperate to confer immunological protection. Using mixed bone marrow chimeras and adoptive transfer studies in which CD8 T cells either do or do not express IL-21R, we discovered that under homeostatic or lymphopenic conditions IL-21 acts directly on CD8 T cells to favor the accumulation of TE/TEM populations. The inability to perceive IL-21 signals under competitive conditions also resulted in lower levels of TRM phenotype cells and reduced expression of granzyme B in the small intestine. IL-21 differentially promoted the expression of the chemokine receptor CX3CR1 and the integrin α4β7 on CD8 T cells primed in vitro and on circulating CD8 T cells in the mixed bone marrow chimeras. The requirement for IL-21 to establish CD8 TE/TEM and TRM subsets was overcome by acute lymphocytic choriomeningitis virus infection; nevertheless, memory virus-specific CD8 T cells remained dependent on IL-21 for optimal accumulation in lymphopenic environments. Overall, this study reveals a context-dependent role for IL-21 in sustaining effector phenotype CD8 T cells and influencing their migratory properties, accumulation, and functions.
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Affiliation(s)
- Yuan Tian
- Department of Microbiology, University of Alabama, Birmingham, AL 35294
| | - Maureen A Cox
- Department of Microbiology, University of Alabama, Birmingham, AL 35294
| | - Shannon M Kahan
- Department of Microbiology, University of Alabama, Birmingham, AL 35294
| | - Jennifer T Ingram
- Department of Microbiology, University of Alabama, Birmingham, AL 35294
| | - Rakesh K Bakshi
- Department of Microbiology, University of Alabama, Birmingham, AL 35294
| | - Allan J Zajac
- Department of Microbiology, University of Alabama, Birmingham, AL 35294
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Sun YY, Peng S, Han L, Qiu J, Song L, Tsai Y, Yang B, Roden RBS, Trimble CL, Hung CF, Wu TC. Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract. Clin Cancer Res 2015; 22:657-69. [PMID: 26420854 DOI: 10.1158/1078-0432.ccr-15-0234] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 09/15/2015] [Indexed: 11/16/2022]
Abstract
PURPOSE Two viral oncoproteins, E6 and E7, are expressed in all human papillomavirus (HPV)-infected cells, from initial infection in the genital tract to metastatic cervical cancer. Intramuscular vaccination of women with high-grade cervical intraepithelial neoplasia (CIN2/3) twice with a naked DNA vaccine, pNGVL4a-sig/E7(detox)/HSP70, and a single boost with HPVE6/E7 recombinant vaccinia vaccine (TA-HPV) elicited systemic HPV-specific CD8 T-cell responses that could traffic to the lesion and was associated with regression in some patients (NCT00788164). EXPERIMENTAL DESIGN Here, we examine whether alteration of this vaccination regimen by administration of TA-HPV vaccination in the cervicovaginal tract, rather than intramuscular (IM) delivery, can more effectively recruit antigen-specific T cells in an orthotopic syngeneic mouse model of HPV16(+) cervical cancer (TC-1 luc). RESULTS We found that pNGVL4a-sig/E7(detox)/HSP70 vaccination followed by cervicovaginal vaccination with TA-HPV increased accumulation of total and E7-specific CD8(+) T cells in the cervicovaginal tract and better controlled E7-expressing cervicovaginal TC-1 luc tumor than IM administration of TA-HPV. Furthermore, the E7-specific CD8(+) T cells in the cervicovaginal tract generated through the cervicovaginal route of vaccination expressed the α4β7 integrin and CCR9, which are necessary for the homing of the E7-specific CD8(+) T cells to the cervicovaginal tract. Finally, we show that cervicovaginal vaccination with TA-HPV can induce potent local HPV-16 E7 antigen-specific CD8(+) T-cell immune responses regardless of whether an HPV DNA vaccine priming vaccination was administered IM or within the cervicovaginal tract. CONCLUSIONS Our results support future clinical translation using cervicovaginal TA-HPV vaccination.
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Affiliation(s)
- Yun-Yan Sun
- Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Shiwen Peng
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Liping Han
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jin Qiu
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Liwen Song
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Yachea Tsai
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Benjamin Yang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Richard B S Roden
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Cornelia L Trimble
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - T-C Wu
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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40
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Nizard M, Diniz MO, Roussel H, Tran T, Ferreira LC, Badoual C, Tartour E. Mucosal vaccines: novel strategies and applications for the control of pathogens and tumors at mucosal sites. Hum Vaccin Immunother 2015; 10:2175-87. [PMID: 25424921 DOI: 10.4161/hv.29269] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The mucosal immune system displays several adaptations reflecting the exposure to the external environment. The efficient induction of mucosal immune responses also requires specific approaches, such as the use of appropriate administration routes and specific adjuvants and/or delivery systems. In contrast to vaccines delivered via parenteral routes, experimental, and clinical evidences demonstrated that mucosal vaccines can efficiently induce local immune responses to pathogens or tumors located at mucosal sites as well as systemic response. At least in part, such features can be explained by the compartmentalization of mucosal B and T cell populations that play important roles in the modulation of local immune responses. In the present review, we discuss molecular and cellular features of the mucosal immune system as well as novel immunization approaches that may lead to the development of innovative and efficient vaccines targeting pathogens and tumors at different mucosal sites.
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Affiliation(s)
- Mevyn Nizard
- a INSERM U970; Universite Paris Descartes; Sorbonne Paris-Cité; Paris, France
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41
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Morales RA, Campos-Mora M, Gajardo T, Pérez F, Campos J, Aguillón JC, Pino-Lagos K. Retinaldehyde dehydrogenase activity is triggered during allograft rejection and it drives Th1/Th17 cytokine production. Immunobiology 2015; 220:769-774. [PMID: 25592248 DOI: 10.1016/j.imbio.2014.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 12/22/2014] [Accepted: 12/23/2014] [Indexed: 01/08/2023]
Abstract
Retinoic acid (RA), a vitamin A metabolite, has been attributed to relevant functions in adaptive immunity. On T cells, the disruption on RA signaling alters both CD4+ and CD8+ T cells effector function. In this study, we evaluated the contribution of RA synthesis during the immune response using an in vivo skin transplantation model. Our data indicates that the frequency and number of cells containing an active retinaldehyde dehydrogenase (RALDH), a key enzyme for RA synthesis, is increased during skin transplant rejection. In addition, we found that the expression of the mRNA coding for the isoform RALDH2 is up-regulated on graft rejecting draining lymph nodes (dLNs) cells. Lastly, we observed that IFN-γ and IL-17 production by ex vivo re-stimulated dLNs cells is greatly increased during rejection, which it turns depends on RA synthesis, as shown in experiments using a specific RALDH inhibitor. Altogether, our data demonstrate that RA synthesis is incremented during the immune response against an allograft, and also indicates that the synthesis of RA is required for cytokine production by dLNs resident T cells.
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Affiliation(s)
- Rodrigo A Morales
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mauricio Campos-Mora
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Tania Gajardo
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Francisco Pérez
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Javier Campos
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Juan C Aguillón
- Immune Regulation and Tolerance Research Group, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile(1)
| | - Karina Pino-Lagos
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
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Guo Y, Brown C, Ortiz C, Noelle RJ. Leukocyte homing, fate, and function are controlled by retinoic acid. Physiol Rev 2015; 95:125-48. [PMID: 25540140 DOI: 10.1152/physrev.00032.2013] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Although vitamin A was recognized as an "anti-infective vitamin" over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell- and humoral-mediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases.
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Affiliation(s)
- Yanxia Guo
- Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire; and Medical Research Council Centre of Transplantation, Guy's Hospital, King's College London, King's Health Partners, London, United Kingdom
| | - Chrysothemis Brown
- Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire; and Medical Research Council Centre of Transplantation, Guy's Hospital, King's College London, King's Health Partners, London, United Kingdom
| | - Carla Ortiz
- Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire; and Medical Research Council Centre of Transplantation, Guy's Hospital, King's College London, King's Health Partners, London, United Kingdom
| | - Randolph J Noelle
- Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire; and Medical Research Council Centre of Transplantation, Guy's Hospital, King's College London, King's Health Partners, London, United Kingdom
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Bekiaris V, Persson EK, Agace WW. Intestinal dendritic cells in the regulation of mucosal immunity. Immunol Rev 2015; 260:86-101. [PMID: 24942684 DOI: 10.1111/imr.12194] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The intestine presents a huge surface area to the outside environment, a property that is of critical importance for its key functions in nutrient digestion, absorption, and waste disposal. As such, the intestine is constantly exposed to dietary and microbial-derived foreign antigens, to which immune cells within the mucosa must suitably respond to maintain intestinal integrity, while also providing the ability to mount effective immune responses to potential pathogens. Dendritic cells (DCs) are sentinel immune cells that play a central role in the initiation and differentiation of adaptive immune responses. In the intestinal mucosa, DCs are located diffusely throughout the intestinal lamina propria, within gut-associated lymphoid tissues, including Peyer's patches and smaller lymphoid aggregates, as well as in intestinal-draining lymph nodes, including mesenteric lymph nodes. The recognition that dietary nutrients and microbial communities in the intestine influence both mucosal and systemic immune cell development and function as well as immune-mediated disease has led to an explosion of literature in mucosal immunology in recent years and a growing interest in the functionality of intestinal DCs. In the current review, we discuss recent findings from our group and others that have provided important insights regarding murine and human intestinal lamina propria DCs and highlighted marked developmental and functional heterogeneity within this compartment. A thorough understanding of the role these subsets play in the regulation of intestinal immune homeostasis and inflammation will help to define novel strategies for the treatment of intestinal pathologies and contribute to improved rational design of mucosal vaccines.
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44
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Chapman NM, Chi H. mTOR Links Environmental Signals to T Cell Fate Decisions. Front Immunol 2015; 5:686. [PMID: 25653651 PMCID: PMC4299512 DOI: 10.3389/fimmu.2014.00686] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 12/20/2014] [Indexed: 12/18/2022] Open
Abstract
T cell fate decisions play an integral role in maintaining the health of organisms under homeostatic and inflammatory conditions. The localized microenvironment in which developing and mature T cells reside provides signals that serve essential functions in shaping these fate decisions. These signals are derived from the immune compartment, including antigens, co-stimulation, and cytokines, and other factors, including growth factors and nutrients. The mechanistic target of rapamycin (mTOR), a vital sensor of signals within the immune microenvironment, is a central regulator of T cell biology. In this review, we discuss how various environmental cues tune mTOR activity in T cells, and summarize how mTOR integrates these signals to influence multiple aspects of T cell biology.
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Affiliation(s)
- Nicole M Chapman
- Department of Immunology, St. Jude Children's Research Hospital , Memphis, TN , USA
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital , Memphis, TN , USA
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45
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46
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Yuan X, Dee MJ, Altman NH, Malek TR. IL-2Rβ-dependent signaling and CD103 functionally cooperate to maintain tolerance in the gut mucosa. THE JOURNAL OF IMMUNOLOGY 2014; 194:1334-46. [PMID: 25527788 DOI: 10.4049/jimmunol.1400955] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A network of mechanisms operates to maintain tolerance in the gut mucosa. Although CD103 marks many lymphoid cells within the gut, its direct functional role in intestinal tolerance is poorly understood. CD103 may be part of a redundant pathway, as CD103(-/-) mice do not exhibit autoimmunity. To reduce such redundancy, CD103(-/-) mice were crossed to mice (designated Y3) whose T cells expressed a mutant IL-2Rβ-chain that lowers IL-2R signaling. Unlike overtly healthy Y3 mice, all Y3/CD103(-/-) mice rapidly developed severe colitis. The large intestine of these mice contained an increase in CD4(+) Th1 and Th17 effector cells and a reduced ratio of regulatory T cells (Tregs). Importantly, colitis was effectively prevented by the transfer of wild-type Tregs into Y3/CD103(-/-) mice. Impaired intestinal tolerance was not attributed to an obvious lack of CD103-dependent gene regulation or intestinal homing/retention by Tregs nor a lack of functional activities typically associated with CD103(+) dendritic cells, such as peripherally induced Treg development or imprinting CCR9 and α4β7 homing molecules on Tregs and T effector cells. Transcriptome analysis of Tregs was consistent with altered homeostasis due to impaired IL-2Rβ-dependent signaling with minimal dysregulation added by the absence of CD103. Rather, the absence of CD103 functioned to alter the localization of the cells within the gut microenvironment that may alter Treg homeostasis. Thus, IL-2Rβ-dependent signaling and CD103 normally cooperate through distinctive processes to promote Treg homeostasis and immune tolerance.
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Affiliation(s)
- Xiaomei Yuan
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101; and
| | - Michael J Dee
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101; and
| | - Norman H Altman
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33101
| | - Thomas R Malek
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101; and
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47
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Goverse G, Olivier BJ, Molenaar R, Knippenberg M, Greuter M, Konijn T, Cook ECL, Beijer MR, Fedor DM, den Haan JMM, Napoli JL, Bouma G, Mebius RE. Vitamin A metabolism and mucosal immune function are distinct between BALB/c and C57BL/6 mice. Eur J Immunol 2014; 45:89-100. [DOI: 10.1002/eji.201343340] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 09/23/2014] [Accepted: 10/08/2014] [Indexed: 12/13/2022]
Affiliation(s)
- Gera Goverse
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Brenda J. Olivier
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Rosalie Molenaar
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Marlene Knippenberg
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Mascha Greuter
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Tanja Konijn
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Emma C. L. Cook
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Marieke R. Beijer
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Dawn M. Fedor
- Department of Gastroenterology; VU University Medical Center; Amsterdam The Netherlands
| | - Joke M. M. den Haan
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
| | - Joseph L. Napoli
- Department of Nutritional Science and Toxicology; University of California; Berkeley CA USA
| | - Gerd Bouma
- Department of Gastroenterology; VU University Medical Center; Amsterdam The Netherlands
| | - Reina E. Mebius
- Department of Molecular Cell Biology and Immunology; VU medical center; Amsterdam The Netherlands
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48
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Bobat S, Cunningham AF. Bacterial infections and vaccines. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 828:75-98. [PMID: 25253028 DOI: 10.1007/978-1-4939-1489-0_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Affiliation(s)
- Saeeda Bobat
- The Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK,
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49
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Burger NB, Stuurman KE, Kok E, Konijn T, Schooneman D, Niederreither K, Coles M, Agace WW, Christoffels VM, Mebius RE, van de Pavert SA, Bekker MN. Involvement of neurons and retinoic acid in lymphatic development: new insights in increased nuchal translucency. Prenat Diagn 2014; 34:1312-9. [PMID: 25088217 DOI: 10.1002/pd.4473] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 07/28/2014] [Accepted: 07/28/2014] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Increased nuchal translucency originates from disturbed lymphatic development. Abnormal neural crest cell (NCC) migration may be involved in lymphatic development. Because both neuronal and lymphatic development share retinoic acid (RA) as a common factor, this study investigated the involvement of NCCs and RA in specific steps in lymphatic endothelial cell (LEC) differentiation and nuchal edema, which is the morphological equivalent of increased nuchal translucency. METHODS Mouse embryos in which all NCCs were fluorescently labeled (Wnt1-Cre;Rosa26(eYfp) ), reporter embryos for in vivo RA activity (DR5-luciferase) and embryos with absent (Raldh2(-/-) ) or in utero inhibition of RA signaling (BMS493) were investigated. Immunofluorescence using markers for blood vessels, lymphatic endothelium and neurons was applied. Flow cytometry was performed to measure specific LEC populations. RESULTS Cranial nerves were consistently close to the jugular lymph sac (JLS), in which NCCs were identified. In the absence of RA synthesis, enlarged JLS and nuchal edema were observed. Inhibiting RA signaling in utero resulted in a significantly higher amount of precursor-LECs at the expense of mature LECs and caused nuchal edema. CONCLUSIONS Neural crest cells are involved in lymphatic development. RA is required for differentiation into mature LECs. Blocking RA signaling in mouse embryos results in abnormal lymphatic development and nuchal edema.
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Affiliation(s)
- Nicole B Burger
- Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands
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Ahmed T, Auble D, Berkley JA, Black R, Ahern PP, Hossain M, Hsieh A, Ireen S, Arabi M, Gordon JI. An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome. Ann N Y Acad Sci 2014; 1332:22-38. [PMID: 25118072 PMCID: PMC4514967 DOI: 10.1111/nyas.12487] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The Sackler Institute for Nutrition Science and the World Health Organization (WHO) have worked together to formulate a research agenda for nutrition science. Undernutrition of children has profound effects on health, development, and achievement of full human capacity. Undernutrition is not simply caused by a lack of food, but results from a complex interplay of intra- and intergenerational factors. Representative preclinical models and comprehensive well-controlled longitudinal clinical studies are needed to further understand the contributions and the interrelationships among these factors and to develop interventions that are effective and durable. This paper summarizes work on mechanisms underlying the varied manifestations of childhood undernutrition and discusses current gaps in knowledge and challenges to our understanding of undernutrition and infection/immunity throughout the human life cycle, focusing on early childhood growth. It proposes a series of basic and clinical studies to address this global health challenge.
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Affiliation(s)
- Tahmeed Ahmed
- Centre for Nutrition and Food Security, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
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