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Lebrusant-Fernandez M, Ap Rees T, Jimeno R, Angelis N, Ng JC, Fraternali F, Li VSW, Barral P. IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells. Cell Rep 2024; 43:114948. [PMID: 39580798 PMCID: PMC11876105 DOI: 10.1016/j.celrep.2024.114948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 09/23/2024] [Accepted: 10/18/2024] [Indexed: 11/26/2024] Open
Abstract
Intestinal homeostasis is maintained through the combined functions of epithelial and immune cells that collaborate to preserve the integrity of the intestinal barrier. However, the mechanisms by which immune cell populations regulate intestinal epithelial cell (IEC) homeostasis remain unclear. Here, we use a multi-omics approach to study the immune-epithelial crosstalk and identify CD1d-restricted natural killer T (NKT) cells as key regulators of IEC biology. We find that NKT cells are abundant in the proximal small intestine and show hallmarks of activation at steady state. Subsequently, NKT cells regulate the survival and the transcriptional and cellular composition landscapes of IECs in intestinal organoids, through interferon-γ (IFN-γ) and interleukin-4 secretion. In vivo, lack of NKT cells results in an increase in IEC turnover, while NKT cell activation leads to IFN-γ-dependent epithelial apoptosis. Our findings propose NKT cells as potent producers of cytokines that contribute to the regulation of IEC homeostasis.
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Affiliation(s)
- Marta Lebrusant-Fernandez
- Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King's College London, London, UK; The Francis Crick Institute, London, UK
| | - Tom Ap Rees
- Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King's College London, London, UK; The Francis Crick Institute, London, UK
| | - Rebeca Jimeno
- Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King's College London, London, UK; The Francis Crick Institute, London, UK
| | | | - Joseph C Ng
- Randall Centre for Cell & Molecular Biophysics, King's College London, London, UK; Institute of Structural and Molecular Biology, University College London, London, UK
| | - Franca Fraternali
- Randall Centre for Cell & Molecular Biophysics, King's College London, London, UK; Institute of Structural and Molecular Biology, University College London, London, UK
| | | | - Patricia Barral
- Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King's College London, London, UK; The Francis Crick Institute, London, UK.
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2
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Yue N, Hu P, Tian C, Kong C, Zhao H, Zhang Y, Yao J, Wei Y, Li D, Wang L. Dissecting Innate and Adaptive Immunity in Inflammatory Bowel Disease: Immune Compartmentalization, Microbiota Crosstalk, and Emerging Therapies. J Inflamm Res 2024; 17:9987-10014. [PMID: 39634289 PMCID: PMC11615095 DOI: 10.2147/jir.s492079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
The intestinal immune system is the largest immune organ in the human body. Excessive immune response to intestinal cavity induced by harmful stimuli including pathogens, foreign substances and food antigens is an important cause of inflammatory diseases such as celiac disease and inflammatory bowel disease (IBD). Although great progress has been made in the treatment of IBD by some immune-related biotherapeutic products, yet a considerable proportion of IBD patients remain unresponsive or immune tolerant to immunotherapeutic strategy. Therefore, it is necessary to further understand the mechanism of immune cell populations involved in enteritis, including dendritic cells, macrophages and natural lymphocytes, in the steady-state immune tolerance of IBD, in order to find effective IBD therapy. In this review, we discussed the important role of innate and adaptive immunity in the development of IBD. And the relationship between intestinal immune system disorders and microflora crosstalk were also presented. We also focus on the new findings in the field of T cell immunity, which might identify novel cytokines, chemokines or anti-cytokine antibodies as new approaches for the treatment of IBD.
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Affiliation(s)
- Ningning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Peng Hu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China
| | - Chengmei Tian
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Chen Kong
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Hailan Zhao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuqi Wei
- Department of Rehabilitation, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Defeng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
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3
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Meinen-Jochum J, Skow CJ, Mellata M. Layer segmented filamentous bacteria colonize and impact gut health of broiler chickens. mSphere 2024; 9:e0049224. [PMID: 39422489 PMCID: PMC11580430 DOI: 10.1128/msphere.00492-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
In commercial poultry farms, chicks hatch away from their progenitors from which they acquire key host-specific microbiota, like segmented filamentous bacteria (SFB) involved in gut maturation in early life. This study investigated whether providing chicken SFB to newly hatched broilers would increase their gut maturation and resistance to bacteria relevant to broiler and human health. One-day-old Ross308 broilers were orally treated with either phosphate-buffered saline (CON) or layer-derived SFB (D-SFB). On days 5, 10, 17, and 24, feces were collected to detect and enumerate SFB and Enterobacteriaceae. On days 8, 15, 22, and 29, birds were euthanized, intestinal samples were collected to detect and enumerate SFB through quantitative PCR (qPCR) and microscopy and expression of genes associated with gut immune function through reverse transcription-qPCR. This study showed that, despite their host specificity, layer SFB can colonize their genetically distinct relative broilers. Ileal SFB colonization was accelerated by a week with the SFB treatment and covered the proximal, medial, and distal sections of the ileum. Colonization of the ileum by SFB in early life highly activated gene expression of intestinal barrier proteins and cytokines, e.g., IL-10 and IFNγ but not IL-17. SFB treatment reduced the level of Enterobacteriaceae in the gut and provided superior resistance to intestinal and extraintestinal pathogens as tested in vitro. Overall, early gut colonization of SFB is imperative for the maturation of the gut immune system and the establishment of a homeostatic gut environment. Improving our understanding of gut immune maturation in food-producing animals is crucial for both human and animal health.IMPORTANCEIn commercial farms, newly hatched chicks may lack host-specific microbiota that help mature their gut immune system for lifelong health benefits. Here, introducing an avian segmented filamentous bacteria (SFB) to commercially sourced chickens orally at hatch accelerated SFB colonization of the ileum. Remarkably, SFB from layers were able to colonize broilers and enhance gut immune maturation, and this immunomodulation impacted the ability to increase intestinal and extraintestinal resistance to bacteria relevant to poultry and human health. With the antibiotic restrictions in animal production, strategies that will help mitigate infections are urgently needed. In summary, we developed a live prophylactic for newly hatched chicks to improve animal health and food safety. Due to the host specificity of SFB, our data highlight the importance of investigating the molecular mechanism of SFB interaction in their own host.
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Affiliation(s)
- Jared Meinen-Jochum
- Interdepartmental Microbiology Graduate Program, Iowa State University, Ames, Iowa, USA
- Department of Food Science and Human Nutrition, Iowa State University, Ames, Iowa, USA
| | - Caleb J. Skow
- Interdepartmental Microbiology Graduate Program, Iowa State University, Ames, Iowa, USA
- Department of Food Science and Human Nutrition, Iowa State University, Ames, Iowa, USA
| | - Melha Mellata
- Interdepartmental Microbiology Graduate Program, Iowa State University, Ames, Iowa, USA
- Department of Food Science and Human Nutrition, Iowa State University, Ames, Iowa, USA
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4
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Chen Y, Xiao L, Zhou M, Zhang H. The microbiota: a crucial mediator in gut homeostasis and colonization resistance. Front Microbiol 2024; 15:1417864. [PMID: 39165572 PMCID: PMC11333231 DOI: 10.3389/fmicb.2024.1417864] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
The gut microbiota is a complex and diverse community of microorganisms that colonizes the human gastrointestinal tract and influences various aspects of human health. These microbes are closely related to enteric infections. As a foreign entity for the host, commensal microbiota is restricted and regulated by the barrier and immune system in the gut and contributes to gut homeostasis. Commensals also effectively resist the colonization of pathogens and the overgrowth of indigenous pathobionts by utilizing a variety of mechanisms, while pathogens have developed strategies to subvert colonization resistance. Dysbiosis of the microbial community can lead to enteric infections. The microbiota acts as a pivotal mediator in establishing a harmonious mutualistic symbiosis with the host and shielding the host against pathogens. This review aims to provide a comprehensive overview of the mechanisms underlying host-microbiome and microbiome-pathogen interactions, highlighting the multi-faceted roles of the gut microbiota in preventing enteric infections. We also discuss the applications of manipulating the microbiota to treat infectious diseases in the gut.
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Affiliation(s)
- Yiding Chen
- Department of Gastroenterology, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Ling Xiao
- Department of Gastroenterology, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Min Zhou
- Department of Gastroenterology, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Tianfu Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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5
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Gutiérrez-Vera C, García-Betancourt R, Palacios PA, Müller M, Montero DA, Verdugo C, Ortiz F, Simon F, Kalergis AM, González PA, Saavedra-Avila NA, Porcelli SA, Carreño LJ. Natural killer T cells in allergic asthma: implications for the development of novel immunotherapeutical strategies. Front Immunol 2024; 15:1364774. [PMID: 38629075 PMCID: PMC11018981 DOI: 10.3389/fimmu.2024.1364774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/06/2024] [Indexed: 04/19/2024] Open
Abstract
Allergic asthma has emerged as a prevalent allergic disease worldwide, affecting most prominently both young individuals and lower-income populations in developing and developed countries. To devise effective and curative immunotherapy, it is crucial to comprehend the intricate nature of this condition, characterized by an immune response imbalance that favors a proinflammatory profile orchestrated by diverse subsets of immune cells. Although the involvement of Natural Killer T (NKT) cells in asthma pathology is frequently implied, their specific contributions to disease onset and progression remain incompletely understood. Given their remarkable ability to modulate the immune response through the rapid secretion of various cytokines, NKT cells represent a promising target for the development of effective immunotherapy against allergic asthma. This review provides a comprehensive summary of the current understanding of NKT cells in the context of allergic asthma, along with novel therapeutic approaches that leverage the functional response of these cells.
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Affiliation(s)
- Cristián Gutiérrez-Vera
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Richard García-Betancourt
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Pablo A. Palacios
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Marioly Müller
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - David A. Montero
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Carlos Verdugo
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Francisca Ortiz
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Noemi A. Saavedra-Avila
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Steven A. Porcelli
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Leandro J. Carreño
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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6
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Lin Q, Kuypers M, Baglaenko Y, Cao E, Hezaveh K, Despot T, de Amat Herbozo C, Cruz Tleugabulova M, Umaña JM, McGaha TL, Philpott DJ, Mallevaey T. The intestinal microbiota modulates the transcriptional landscape of iNKT cells at steady-state and following antigen exposure. Mucosal Immunol 2024; 17:226-237. [PMID: 38331095 DOI: 10.1016/j.mucimm.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/10/2024]
Abstract
Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to microbe-derived glycolipid antigens. iNKT cells exert fast innate effector functions that regulate immune responses in a variety of contexts, including during infection, cancer, or inflammation. The roles these unconventional T cells play in intestinal inflammation remain poorly defined and vary based on the disease model and species. Our previous work suggested that the gut microbiota influenced iNKT cell functions during dextran sulfate sodium-induced colitis in mice. This study, shows that iNKT cell homeostasis and response following activation are altered in germ-free mice. Using prenatal fecal transplant in specific pathogen-free mice, we show that the transcriptional signatures of iNKT cells at steady state and following αGC-mediated activation in vivo are modulated by the microbiota. Our data suggest that iNKT cells sense the microbiota at homeostasis independently of their T cell receptors. Finally, iNKT cell transcriptional signatures are different in male and female mice. Collectively, our findings suggest that sex and the intestinal microbiota are important factors that regulate iNKT cell homeostasis and responses. A deeper understanding of microbiota-iNKT cell interactions and the impact of sex could improve the development of iNKT cell-based immunotherapies.
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Affiliation(s)
- Qiaochu Lin
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Meggie Kuypers
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Yuriy Baglaenko
- Center for Autoimmune Genomics and Etiology, Division of Genetics, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Eric Cao
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Kebria Hezaveh
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Tijana Despot
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | - Tracy L McGaha
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Thierry Mallevaey
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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7
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Cui G, Abe S, Kato R, Ikuta K. Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues. Front Immunol 2024; 15:1349184. [PMID: 38440725 PMCID: PMC10910067 DOI: 10.3389/fimmu.2024.1349184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/06/2024] [Indexed: 03/06/2024] Open
Abstract
Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.
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Affiliation(s)
- Guangwei Cui
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Shinya Abe
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Ryoma Kato
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Koichi Ikuta
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
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8
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Lee SW, Park HJ, Van Kaer L, Hong S. Role of CD1d and iNKT cells in regulating intestinal inflammation. Front Immunol 2024; 14:1343718. [PMID: 38274786 PMCID: PMC10808723 DOI: 10.3389/fimmu.2023.1343718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 12/26/2023] [Indexed: 01/27/2024] Open
Abstract
Invariant natural killer T (iNKT) cells, a subset of unconventional T cells that recognize glycolipid antigens in a CD1d-dependent manner, are crucial in regulating diverse immune responses such as autoimmunity. By engaging with CD1d-expressing non-immune cells (such as intestinal epithelial cells and enterochromaffin cells) and immune cells (such as type 3 innate lymphoid cells, B cells, monocytes and macrophages), iNKT cells contribute to the maintenance of immune homeostasis in the intestine. In this review, we discuss the impact of iNKT cells and CD1d in the regulation of intestinal inflammation, examining both cellular and molecular factors with the potential to influence the functions of iNKT cells in inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
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Affiliation(s)
- Sung Won Lee
- Department of Biomedical Laboratory Science, College of Health and Biomedical Services, Sangji University, Wonju, Republic of Korea
| | - Hyun Jung Park
- Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul, Republic of Korea
| | - Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Seokmann Hong
- Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul, Republic of Korea
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9
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Díaz-Basabe A, Lattanzi G, Perillo F, Amoroso C, Baeri A, Farini A, Torrente Y, Penna G, Rescigno M, Ghidini M, Cassinotti E, Baldari L, Boni L, Vecchi M, Caprioli F, Facciotti F, Strati F. Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion. Gut Microbes 2024; 16:2388801. [PMID: 39132842 PMCID: PMC11321422 DOI: 10.1080/19490976.2024.2388801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/19/2024] [Accepted: 07/31/2024] [Indexed: 08/13/2024] Open
Abstract
The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). The pathobiont Fusobacterium nucleatum influences the anti-tumor functions of CRC-infiltrating iNKT cells. However, the impact of other bacteria associated with CRC, like Porphyromonas gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumor microenvironment. Mechanistically, in vivo and in vitro experiments showed that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery through increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing the upregulation of CHI3L1 in iNKT cells, thus impairing their cytotoxic functions and promoting host tumor immune evasion.
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Affiliation(s)
- Angélica Díaz-Basabe
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Georgia Lattanzi
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Perillo
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Chiara Amoroso
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Alberto Baeri
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Andrea Farini
- Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Yvan Torrente
- Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Centro Dino Ferrari, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Giuseppe Penna
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Maria Rescigno
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Michele Ghidini
- Medical Oncology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Elisa Cassinotti
- Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Ludovica Baldari
- Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Luigi Boni
- Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Francesco Strati
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
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10
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Parihar N, Bhatt LK. The emerging paradigm of Unconventional T cells as a novel therapeutic target for celiac disease. Int Immunopharmacol 2023; 122:110666. [PMID: 37473709 DOI: 10.1016/j.intimp.2023.110666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/07/2023] [Accepted: 07/16/2023] [Indexed: 07/22/2023]
Abstract
Celiac disease (CD) is an organ-specific autoimmune disorder that occurs in genetically predisposed individuals when exposed to exogenous dietary gluten. This exposure to wheat gluten and related proteins from rye and barley triggers an immune response which leads to the development of enteropathy associated with symptoms of bloating, diarrhea, or malabsorption. The sole current treatment is to follow a gluten-free diet for the rest of one's life. Intestinal barriers are enriched with Unconventional T cells such as iNKT, MAIT, and γδ T cells, which lack or express only a limited range of rearranged antigen receptors. Unconventional T cells play a crucial role in regulating mucosal barrier function and microbial colonization. Unconventional T cell populations are widely represented in diseased conditions, where changes in disease activity related to iNKT and MAIT cell reduction, as well as γδ T cell expansion, are demonstrated. In this review, we discuss the role and potential employment of Unconventional T cells as a therapeutic target in the pathophysiology of celiac disease.
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Affiliation(s)
- Niraj Parihar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India.
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11
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Luo J, Chen Z, Castellano D, Bao B, Han W, Li J, Kim G, An D, Lu W, Wu C. Lipids regulate peripheral serotonin release via gut CD1d. Immunity 2023; 56:1533-1547.e7. [PMID: 37354904 PMCID: PMC10527042 DOI: 10.1016/j.immuni.2023.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/04/2023] [Accepted: 06/01/2023] [Indexed: 06/26/2023]
Abstract
The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.
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Affiliation(s)
- Jialie Luo
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Zuojia Chen
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - David Castellano
- Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Bin Bao
- Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wenyan Han
- Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Jian Li
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Girak Kim
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Dingding An
- Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wei Lu
- Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
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12
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Joyce S, Okoye GD, Driver JP. Die Kämpfe únd schláchten-the struggles and battles of innate-like effector T lymphocytes with microbes. Front Immunol 2023; 14:1117825. [PMID: 37168859 PMCID: PMC10165076 DOI: 10.3389/fimmu.2023.1117825] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/22/2023] [Indexed: 05/13/2023] Open
Abstract
The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the αβ T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes-here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not. Even though the innate/innate-like lymphocytes express rearranged, adaptive antigen-specific receptors, they behave like innate immune cells, which allows them to integrate sensory signals from the innate immune system and relay that umwelt to downstream innate and adaptive effector responses. Here, we review natural killer T cells and mucosal-associated invariant T cells-two prototypic innate-like T lymphocytes, which sense their local environment and relay that umwelt to downstream innate and adaptive effector cells to actuate an appropriate host response that confers immunity to infectious agents.
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Affiliation(s)
- Sebastian Joyce
- Department of Veterans Affairs, Tennessee Valley Healthcare Service, Nashville, TN, United States
- Department of Pathology, Microbiology and Immunology, The Vanderbilt Institute for Infection, Immunology and Inflammation and Vanderbilt Center for Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Gosife Donald Okoye
- Department of Pathology, Microbiology and Immunology, The Vanderbilt Institute for Infection, Immunology and Inflammation and Vanderbilt Center for Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - John P. Driver
- Division of Animal Sciences, University of Missouri, Columbia, MO, United States
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13
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Chen Q, Wang M, Han M, Xu L, Zhang H. Molecular basis of Klebsiella pneumoniae colonization in host. Microb Pathog 2023; 177:106026. [PMID: 36773942 DOI: 10.1016/j.micpath.2023.106026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 02/03/2023] [Accepted: 02/05/2023] [Indexed: 02/12/2023]
Abstract
Klebsiella pneumoniae (K. pneumoniae) is a common cause of nosocomial infection, which causing disseminated infections such as cystitis, pneumonia and sepsis. K. pneumoniae is intrinsic resistant to penicillin, and members of the population usually have acquired resistance to a variety of antibiotics, which makes it a major threat to clinical and public health. Bacteria can colonize on or within the hosts, accompanied by growth and reproduction of the organisms, but no clinical symptoms are presented. As the "first step" of bacterial infection, colonization in the hosts is of great importance. Colonization of bacteria can last from days to years, with resolution influenced by immune response to the organism, competition at the site from other organisms and, sometimes, use of antimicrobials. Colonized pathogenic bacteria cause healthcare-associated infections at times of reduced host immunity, which is an important cause of clinical occurrence of postoperative complications and increased mortality in ICU patients. Though, K. pneumoniae is one of the most common conditional pathogens of hospital-acquired infections, the mechanisms of K. pneumoniae colonization in humans are not completely clear. In this review, we made a brief summary of the molecular basis of K. pneumoniae colonization in the upper respiratory tract and intestinal niche, and provided new insights for understanding the pathogenesis of K. pneumoniae.
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Affiliation(s)
- Qi Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Mingxiao Han
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Leyi Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Haifang Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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14
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Shinton SA, Brill-Dashoff J, Hayakawa K. Pla2g2a promotes innate Th2-type immunity lymphocytes to increase B1a cells. Sci Rep 2022; 12:14899. [PMID: 36050343 PMCID: PMC9437038 DOI: 10.1038/s41598-022-18876-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/22/2022] [Indexed: 11/09/2022] Open
Abstract
Newborns require early generation of effective innate immunity as a primary physiological mechanism for survival. The neonatal Lin28+Let7– developmental pathway allows increased generation of Th2-type cells and B1a (B-1 B) cells compared to adult cells and long-term maintenance of these initially generated innate cells. For initial B1a cell growth from the neonatal to adult stage, Th2-type IL-5 production from ILC2s and NKT2 cells is important to increase B1a cells. The Th17 increase is dependent on extracellular bacteria, and increased bacteria leads to lower Th2-type generation. Secreted group IIA-phospholipase A2 (sPLA2-IIA) from the Pla2g2a gene can bind to gram-positive bacteria and degrade bacterial membranes, controlling microbiota in the intestine. BALB/c mice are Pla2g2a+, and express high numbers of Th2-type cells and B1a cells. C57BL/6 mice are Pla2g2a-deficient and distinct from the SLAM family, and exhibit fewer NKT2 cells and fewer B1a cells from the neonatal to adult stage. We found that loss of Pla2g2a in the BALB/c background decreased IL-5 from Th2-type ILC2s and NKT2s but increased bacterial-reactive NKT17 cells and MAIT cells, and decreased the number of early-generated B1a cells and MZ B cells and the CD4/CD8 T cell ratio. Low IL-5 by decreased Th2-type cells in Pla2g2a loss led to low early-generated B1a cell growth from the neonatal to adult stage. In anti-thymocyte/Thy-1 autoreactive μκ transgenic (ATAμκ Tg) Pla2g2a+ BALB/c background C.B17 mice generated NKT2 cells that continuously control CD1d+ B1 B cells through old aging and lost CD1d in B1 B cells generating strong B1 ATA B cell leukemia/lymphoma. Pla2g2a-deficient ATAμκTg C57BL/6 mice suppressed the initial B1a cell increase, with low/negative spontaneous leukemia/lymphoma generation. These data confirmed that the presence of Pla2g2a to control bacteria is important to allow the neonatal to adult stage. Pla2g2a promotes innate Th2-type immunity lymphocytes to increase early generated B1a cells.
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Affiliation(s)
- Susan A Shinton
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA
| | | | - Kyoko Hayakawa
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA.
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15
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Lin Q, Kuypers M, Liu Z, Copeland JK, Chan D, Robertson SJ, Kontogiannis J, Guttman DS, Banks EK, Philpott DJ, Mallevaey T. Invariant natural killer T cells minimally influence gut microbiota composition in mice. Gut Microbes 2022; 14:2104087. [PMID: 35912530 PMCID: PMC9348128 DOI: 10.1080/19490976.2022.2104087] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to glycolipid antigens found in microbes in a CD1d-dependent manner. iNKT cells exert innate-like functions and produce copious amounts of cytokines, chemokines and cytotoxic molecules within only minutes of activation. As such, iNKT cells can fuel or dampen inflammation in a context-dependent manner. In addition, iNKT cells provide potent immunity against bacteria, viruses, parasites and fungi. Although microbiota-iNKT cell interactions are not well-characterized, mounting evidence suggests that microbiota colonization early in life impacts iNKT cell homeostasis and functions in disease. In this study, we showed that CD1d-/- and Vα14 Tg mice, which lack and have increased numbers of iNKT cells, respectively, had no significant alterations in gut microbiota composition compared to their littermate controls. Furthermore, specific iNKT cell activation by glycolipid antigens only resulted in a transient and minimal shift in microbiota composition when compared to the natural drift found in our colony. Our findings demonstrate that iNKT cells have little to no influence in regulating commensal bacteria at steady state.Abbreviations: iNKT: invariant Natural Killer T cell; αGC: α-galactosylceramide.
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Affiliation(s)
- Qiaochu Lin
- Department of Immunology, University of Toronto, Toronto, ON, Canada,CONTACT Thierry Mallevaey University of Toronto, Department of Immunology, Medical Sciences Building, Room 7334,1 King’s College Circle, Toronto, OntarioM5S 1A8, Canada
| | - Meggie Kuypers
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Zhewei Liu
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Julia K Copeland
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
| | - Donny Chan
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
| | - Susan J Robertson
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Jean Kontogiannis
- Division of Comparative Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - David S Guttman
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada,Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada
| | - E. Kate Banks
- Division of Comparative Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada,Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Thierry Mallevaey
- Department of Immunology, University of Toronto, Toronto, ON, Canada,Institute of Biomaterials & Biomedical Engineering, University of Toronto, Toronto, ON, Canada
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16
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Abstract
The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. We now appreciate that the coevolution of the immune system and the microbiota has led to development of a lush immunological decision tree downstream of microbial recognition, of which an inflammatory response is but one branch. In this review we discuss known T cell-microbe interactions in the gut and place them in the context of an algorithmic framework of recognition, context-dependent interpretation, and response circuits across multiple levels of microbial recognition resolution. The malleability of T cells in response to the microbiota presents an opportunity to edit immune response cellularity, identity, and functionality by utilizing microbiota-controlled pathways to promote human health.
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Affiliation(s)
- Ivaylo I Ivanov
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA;
| | - Timur Tuganbaev
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Ashwin N Skelly
- Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kenya Honda
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
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17
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Abstract
The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. We now appreciate that the coevolution of the immune system and the microbiota has led to development of a lush immunological decision tree downstream of microbial recognition, of which an inflammatory response is but one branch. In this review we discuss known T cell-microbe interactions in the gut and place them in the context of an algorithmic framework of recognition, context-dependent interpretation, and response circuits across multiple levels of microbial recognition resolution. The malleability of T cells in response to the microbiota presents an opportunity to edit immune response cellularity, identity, and functionality by utilizing microbiota-controlled pathways to promote human health.
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Affiliation(s)
- Ivaylo I Ivanov
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA;
| | - Timur Tuganbaev
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Ashwin N Skelly
- Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kenya Honda
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
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18
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Govers C, Calder PC, Savelkoul HFJ, Albers R, van Neerven RJJ. Ingestion, Immunity, and Infection: Nutrition and Viral Respiratory Tract Infections. Front Immunol 2022; 13:841532. [PMID: 35296080 PMCID: PMC8918570 DOI: 10.3389/fimmu.2022.841532] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/02/2022] [Indexed: 12/12/2022] Open
Abstract
Respiratory infections place a heavy burden on the health care system, particularly in the winter months. Individuals with a vulnerable immune system, such as very young children and the elderly, and those with an immune deficiency, are at increased risk of contracting a respiratory infection. Most respiratory infections are relatively mild and affect the upper respiratory tract only, but other infections can be more serious. These can lead to pneumonia and be life-threatening in vulnerable groups. Rather than focus entirely on treating the symptoms of infectious disease, optimizing immune responsiveness to the pathogens causing these infections may help steer towards a more favorable outcome. Nutrition may have a role in such prevention through different immune supporting mechanisms. Nutrition contributes to the normal functioning of the immune system, with various nutrients acting as energy sources and building blocks during the immune response. Many micronutrients (vitamins and minerals) act as regulators of molecular responses of immune cells to infection. It is well described that chronic undernutrition as well as specific micronutrient deficiencies impair many aspects of the immune response and make individuals more susceptible to infectious diseases, especially in the respiratory and gastrointestinal tracts. In addition, other dietary components such as proteins, pre-, pro- and synbiotics, and also animal- and plant-derived bioactive components can further support the immune system. Both the innate and adaptive defense systems contribute to active antiviral respiratory tract immunity. The initial response to viral airway infections is through recognition by the innate immune system of viral components leading to activation of adaptive immune cells in the form of cytotoxic T cells, the production of neutralizing antibodies and the induction of memory T and B cell responses. The aim of this review is to describe the effects of a range different dietary components on anti-infective innate as well as adaptive immune responses and to propose mechanisms by which they may interact with the immune system in the respiratory tract.
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Affiliation(s)
- Coen Govers
- Cell Biology and Immunology, Wageningen University and Research, Wageningen, Netherlands
| | - Philip C. Calder
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - Huub F. J. Savelkoul
- Cell Biology and Immunology, Wageningen University and Research, Wageningen, Netherlands
| | | | - R. J. Joost van Neerven
- Cell Biology and Immunology, Wageningen University and Research, Wageningen, Netherlands
- Research & Development, FrieslandCampina, Amersfoort, Netherlands
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19
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Cairo C, Webb TJ. Effective Barriers: The Role of NKT Cells and Innate Lymphoid Cells in the Gut. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:235-246. [PMID: 35017213 DOI: 10.4049/jimmunol.2100799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/19/2021] [Indexed: 06/14/2023]
Abstract
The critical role of commensal microbiota in regulating the host immune response has been established. In addition, it is known that host-microbial interactions are bidirectional, and this interplay is tightly regulated to prevent chronic inflammatory disease. Although many studies have focused on the role of classic T cell subsets, unconventional lymphocytes such as NKT cells and innate lymphoid cells also contribute to the regulation of homeostasis at mucosal surfaces and influence the composition of the intestinal microbiota. In this review, we discuss the mechanisms involved in the cross-regulation between NKT cells, innate lymphoid cells, and the gut microbiota. Moreover, we highlight how disruptions in homeostasis can lead to immune-mediated disorders.
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Affiliation(s)
- Cristiana Cairo
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD;
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD
| | - Tonya J Webb
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD; and
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD
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20
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α-Galactosylceramide-Reactive NKT Cells Increase IgG1 Class Switch against a Clostridioides difficile Polysaccharide Antigen and Enhance Immunity against a Live Pathogen Challenge. Infect Immun 2021; 89:e0043821. [PMID: 34424751 DOI: 10.1128/iai.00438-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
All clinical Clostridioides difficile strains identified to date express a surface capsule-like polysaccharide structure known as polysaccharide II (PSII). The PSII antigen is immunogenic and, when conjugated to a protein carrier, induces a protective antibody response in animal models. Given that CD1d-restricted natural killer T (NKT) cells promote antibody responses, including those against carbohydrates, we tested the hypothesis that immunization with PSII and a CD1d-binding glycolipid adjuvant could lead to enhanced protection against a live C. difficile challenge. We purified PSII from a clinical isolate of C. difficile and immunized B6 mice with PSII alone or PSII plus the CD1d-binding glycolipid α-galactosylceramide (α-GC). PSII-specific IgM and IgG titers were evident in sera from immunized mice. The inclusion of α-GC had a modest influence on isotype switch but increased the IgG1/IgG2c ratio. Enhanced protection against C. difficile disease was achieved by inclusion of the α-GC ligand and was associated with reduced bacterial numbers in fecal pellets. In contrast, NKT-deficient Traj18-/- mice were not protected by the PSII/α-GC immunization modality. Absence of NKT cells similarly had a modest effect on isotype switch, but ratios of IgG1/IgG2c decreased. These results indicate that α-GC-driven NKT cells move the humoral immune response against C. difficile PSII antigen toward Th2-driven IgG1 and may contribute to augmented protection. This study suggests that NKT activation represents a pathway for additional B-cell help that could be used to supplement existing efforts to develop vaccines against polysaccharides derived from C. difficile and other pathogens.
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21
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Vogt S, Mattner J. NKT Cells Contribute to the Control of Microbial Infections. Front Cell Infect Microbiol 2021; 11:718350. [PMID: 34595131 PMCID: PMC8477047 DOI: 10.3389/fcimb.2021.718350] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/25/2021] [Indexed: 12/14/2022] Open
Abstract
Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.
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Affiliation(s)
- Stefan Vogt
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
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22
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Kayama H, Okumura R, Takeda K. Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine. Annu Rev Immunol 2021; 38:23-48. [PMID: 32340570 DOI: 10.1146/annurev-immunol-070119-115104] [Citation(s) in RCA: 419] [Impact Index Per Article: 104.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The gastrointestinal tract harbors numerous commensal bacteria, referred to as the microbiota, that benefit host health by digesting dietary components and eliminating pathogens. The intestinal microbiota maintains epithelial barrier integrity and shapes the mucosal immune system, balancing host defense and oral tolerance with microbial metabolites, components, and attachment to host cells. To avoid aberrant immune responses, epithelial cells segregate the intestinal microbiota from immune cells by constructing chemical and physical barriers, leading to the establishment of host-commensal mutualism. Furthermore, intestinal immune cells participate in the maintenance of a healthy microbiota community and reinforce epithelial barrier functions. Perturbations of the microbiota composition are commonly observed in patients with autoimmune diseases and chronic inflammatory disorders. An understanding of the intimate interactions between the intestinal microbiota, epithelial cells, and immune cells that are crucial for the maintenance of intestinal homeostasis might promote advances in diagnostic and therapeutic approaches for various diseases.
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Affiliation(s)
- Hisako Kayama
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; , , .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.,Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ryu Okumura
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; , , .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; , , .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
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23
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Vomhof-DeKrey EE, Stover A, Basson MD. Microbiome diversity declines while distinct expansions of Th17, iNKT, and dendritic cell subpopulations emerge after anastomosis surgery. Gut Pathog 2021; 13:51. [PMID: 34376235 PMCID: PMC8353768 DOI: 10.1186/s13099-021-00447-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/30/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Anastomotic failure causes morbidity and mortality even in technically correct anastomoses. Initial leaks must be prevented by mucosal reapproximation across the anastomosis. Healing is a concerted effort between intestinal epithelial cells (IECs), immune cells, and commensal bacteria. IEC TLR4 activation and signaling is required for mucosal healing, leading to inflammatory factor release that recruits immune cells to limit bacteria invasion. TLR4 absence leads to mucosal damage from loss in epithelial proliferation, attenuated inflammatory response, and bacteria translocation. We hypothesize after anastomosis, an imbalance in microbiota will occur due to a decrease in TLR4 expression and will lead to changes in the immune milieu. RESULTS We isolated fecal content and small intestinal leukocytes from murine, Roux-en-Y and end-to-end anastomoses, to identify microbiome changes and subsequent alterations in the regulatory and pro-inflammatory immune cells 3 days post-operative. TLR4+ IECs were impaired after anastomosis. Microbiome diversity was reduced, with Firmicutes, Bacteroidetes, and Saccharibacteria decreased and Proteobacteria increased. A distinct TCRβhi CD4+ T cells subset after anastomosis was 10-20-fold greater than in control mice. 84% were Th17 IL-17A/F+ IL-22+ and/or TNFα+. iNKT cells were increased and TCRβhi. 75% were iNKT IL-10+ and 13% iNKTh17 IL-22+. Additionally, Treg IL-10+ and IL-22+ cells were increased. A novel dendritic cell subset was identified in anastomotic regions that was CD11bhi CD103mid and was 93% IL-10+. CONCLUSIONS This anastomotic study demonstrated a decrease in IEC TLR4 expression and microbiome diversity which then coincided with increased expansion of regulatory and pro-inflammatory immune cells and cytokines. Defining the anastomotic mucosal environment could help inform innovative therapeutics to target excessive pro-inflammatory invasion and microbiome imbalance.
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Affiliation(s)
- Emilie E. Vomhof-DeKrey
- Department of Surgery, University of North Dakota School of Medicine and the Health Sciences, 1301 North Columbia Road, Stop 9037, Grand Forks, ND 58202 USA
- Department of Biomedical Sciences, University of North Dakota School of Medicine and the Health Sciences, 1301 North Columbia Road, Stop 9037, Grand Forks, ND 58202 USA
| | - Allie Stover
- Department of Biomedical Sciences, University of North Dakota School of Medicine and the Health Sciences, 1301 North Columbia Road, Stop 9037, Grand Forks, ND 58202 USA
| | - Marc D. Basson
- Department of Surgery, University of North Dakota School of Medicine and the Health Sciences, 1301 North Columbia Road, Stop 9037, Grand Forks, ND 58202 USA
- Department of Biomedical Sciences, University of North Dakota School of Medicine and the Health Sciences, 1301 North Columbia Road, Stop 9037, Grand Forks, ND 58202 USA
- Department of Pathology, University of North Dakota School of Medicine and the Health Sciences, 1301 North Columbia Road, Stop 9037, Grand Forks, ND 58202 USA
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24
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Bertrand L, Toubal A, Lehuen A. Macrophages make the bed for early iNKT cells. Nat Immunol 2021; 22:681-682. [PMID: 34040227 DOI: 10.1038/s41590-021-00938-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Léo Bertrand
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.,Laboratoire d'Excellence Inflamex, Paris, France
| | - Amine Toubal
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.,Laboratoire d'Excellence Inflamex, Paris, France
| | - Agnès Lehuen
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France. .,Laboratoire d'Excellence Inflamex, Paris, France.
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25
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Type II NKT Cell Agonist, Sulfatide, Is an Effective Adjuvant for Oral Heat-Killed Cholera Vaccines. Vaccines (Basel) 2021; 9:vaccines9060619. [PMID: 34201310 PMCID: PMC8230052 DOI: 10.3390/vaccines9060619] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Oral vaccination has the potential to offer a safer and more efficacious approach for protection against enteric pathogens than injection-based approaches, especially in developing countries. One key advantage is the potential to induce intestinal immune responses in addition to systemic immunity. In general, antigen delivery via the oral route triggers weak immune responses or immunological tolerance. The effectiveness of oral vaccination can be improved by co-administering adjuvants. However, a major challenge is the absence of potent and safe oral adjuvants for clinical application. Here, the Type II NKT cell activator sulfatide is shown for the first time to be an effective oral adjuvant for Vibrio cholerae vaccine antigens in a mouse model. Specifically, administration of sulfatide with the oral cholera vaccine Dukoral® resulted in enhancement of intestinal antigen-specific IgA in addition to Th1 and Th17 immune responses. In summary, sulfatide is a promising adjuvant for inclusion in an oral cholera vaccine and our data further support the potential of adjuvants targeting NKT cells in new vaccine strategies.
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26
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Gensollen T, Lin X, Zhang T, Pyzik M, See P, Glickman JN, Ginhoux F, Waldor M, Salmi M, Rantakari P, Blumberg RS. Embryonic macrophages function during early life to determine invariant natural killer T cell levels at barrier surfaces. Nat Immunol 2021; 22:699-710. [PMID: 34040226 PMCID: PMC8171892 DOI: 10.1038/s41590-021-00934-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 04/16/2021] [Indexed: 12/24/2022]
Abstract
It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.
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Affiliation(s)
- Thomas Gensollen
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Xi Lin
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Ting Zhang
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,Howard Hughes Medical Institute, Boston, MA 02115, USA
| | - Michal Pyzik
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Peter See
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
| | - Jonathan N. Glickman
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Florent Ginhoux
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
| | - Matthew Waldor
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,Howard Hughes Medical Institute, Boston, MA 02115, USA
| | - Marko Salmi
- Institute of Biomedicine, University of Turku, Turku, FI-20520, Finland,MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland
| | - Pia Rantakari
- Institute of Biomedicine, University of Turku, Turku, FI-20520, Finland,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, FI-20520, Finland
| | - Richard S. Blumberg
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,Correspondence to:
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27
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Abstract
The immune system has coevolved with extensive microbial communities living on barrier sites that are collectively known as the microbiota. It is increasingly clear that microbial antigens and metabolites engage in a constant dialogue with the immune system, leading to microbiota-specific immune responses that occur in the absence of inflammation. This form of homeostatic immunity encompasses many arms of immunity, including B cell responses, innate-like T cells, and conventional T helper and T regulatory responses. In this review we summarize known examples of innate-like T cell and adaptive immunity to the microbiota, focusing on fundamental aspects of commensal immune recognition across different barrier sites. Furthermore, we explore how this cross talk is established during development, emphasizing critical temporal windows that establish long-term immune function. Finally, we highlight how dysregulation of immunity to the microbiota can lead to inflammation and disease, and we pinpoint outstanding questions and controversies regarding immune system-microbiota interactions.
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Affiliation(s)
- Eduard Ansaldo
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20814, USA;
| | - Taylor K Farley
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20814, USA; .,Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20814, USA; .,Microbiome Program, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA
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28
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Zong X, Fu J, Xu B, Wang Y, Jin M. Interplay between gut microbiota and antimicrobial peptides. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2020; 6:389-396. [PMID: 33364454 PMCID: PMC7750803 DOI: 10.1016/j.aninu.2020.09.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/19/2022]
Abstract
The gut microbiota is comprised of a diverse array of microorganisms that interact with immune system and exert crucial roles for the health. Changes in the gut microbiota composition and functionality are associated with multiple diseases. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Major players in this scenario are antimicrobial peptides (AMP), which belong to an ancient defense system found in all organisms and participate in a preservative co-evolution with a complex microbiome. Particularly increasing interactions between AMP and microbiota have been found in the gut. Here, we focus on the mechanisms by which AMP help to maintain a balanced microbiota and advancing our understanding of the circumstances of such balanced interactions between gut microbiota and host AMP. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota, which should have therapeutic implications for different intestinal disorders.
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Affiliation(s)
- Xin Zong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jie Fu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bocheng Xu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yizhen Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Mingliang Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
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29
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Lin Q, Kuypers M, Philpott DJ, Mallevaey T. The dialogue between unconventional T cells and the microbiota. Mucosal Immunol 2020; 13:867-876. [PMID: 32704035 DOI: 10.1038/s41385-020-0326-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 06/19/2020] [Accepted: 06/19/2020] [Indexed: 02/04/2023]
Abstract
The mammalian immune system is equipped with unconventional T cells that respond to microbial molecules such as glycolipids and small-molecule metabolites, which are invisible to conventional CD4 and CD8 T cells. Unconventional T cells include invariant natural killer T (iNKT) cells and mucosa-associated invariant T (MAIT) cells, which are involved in a wide range of infectious and non-infectious diseases, such as cancer and autoimmunity. In addition, their high conservation across mammals, their restriction by non-polymorphic antigen-presenting molecules, and their immediate and robust responses make these 'innate' T cells appealing targets for the development of one-size-fits-all immunotherapies. In this review, we discuss how iNKT and MAIT cells directly and indirectly detect the presence of and respond to pathogenic and commensal microbes. We also explore the current understanding of the bidirectional relationship between the microbiota and innate T cells, and how this crosstalk shapes the immune response in disease.
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Affiliation(s)
- Qiaochu Lin
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Meggie Kuypers
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Thierry Mallevaey
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. .,Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
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30
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Cui S, Wang C, Bai W, Li J, Pan Y, Huang X, Yang H, Feng Z, Xiang Q, Fei L, Zheng L, Huang J, Zhang Q, Wu Y, Chen Y. CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation. SCIENCE ADVANCES 2020; 6:6/43/eaaz7290. [PMID: 33087357 PMCID: PMC7577718 DOI: 10.1126/sciadv.aaz7290] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 09/08/2020] [Indexed: 06/11/2023]
Abstract
Dysregulation of immune responses in the gut often associates with inflammatory bowel diseases (IBD). Mouse CD1d1, an ortholog of human CD1d mainly participating in lipid-antigen presentation to NKT cells, is able to generate intrinsic signals upon stimulation. Mice with macrophage-specific CD1d1 deficiency (LymCD1d1-/- ) acquire resistance to dextran sodium sulfate (DSS)-induced colitis, attributing to the transcriptional inhibition of NLRP3 inflammasome components. The hyperactivation of NLRP3 inflammasome accounts for gut epithelial proliferation and intestine-blood barrier integrity. Mechanistically, occupancy by the natural ligand glycosphingolipid iGb3, CD1d1 responds with intracellular Ser330 dephosphorylation thus to reduce the Peroxiredoxin 1 (PRDX1)-associated AKT-STAT1 phosphorylation and subsequent NF-κB activation, eventually causing transcriptional down-regulation of Nlrp3 and its immediate substrates Il1b and Il18 in macrophages. Therefore, the counterbalancing role of CD1d1 in macrophages appears to determine severity of DSS-mediated colitis in mice. These findings propose new intervention strategies for treating IBD and other inflammatory disorders.
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Affiliation(s)
- Shan Cui
- Yanbian University Hospital, Yanbian University, Jilin Province 133000, People's Republic of China
| | - Chenhui Wang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Weizhi Bai
- Department of Emergency, Chongqing University Center Hospital, Chongqing Emergency Medical Center, Chongqing 400038, People's Republic of China
| | - Jiao Li
- School of Medicine, Yanbian University, Jilin Province 133000, People's Republic of China
| | - Yue Pan
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Xiaoyong Huang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Han Yang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Zeqing Feng
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Qun Xiang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Lei Fei
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Lixin Zheng
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - Jian Huang
- Department of Emergency, Chongqing University Center Hospital, Chongqing Emergency Medical Center, Chongqing 400038, People's Republic of China.
| | - Qinggao Zhang
- School of Medicine, Yanbian University, Jilin Province 133000, People's Republic of China.
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China.
| | - Yongwen Chen
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China.
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31
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Microbiome in Multiple Sclerosis; Where Are We, What We Know and Do Not Know. Brain Sci 2020; 10:brainsci10040234. [PMID: 32295236 PMCID: PMC7226078 DOI: 10.3390/brainsci10040234] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
An increase of multiple sclerosis (MS) incidence has been reported during the last decade, and this may be connected to environmental factors. This review article aims to encapsulate the current advances targeting the study of the gut-brain axis, which mediates the communication between the central nervous system and the gut microbiome. Clinical data arising from many research studies, which have assessed the effects of administered disease-modifying treatments in MS patients to the gut microbiome, are also recapitulated.
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32
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de Aguiar CF, Castoldi A, Amano MT, Ignacio A, Terra FF, Cruz M, Felizardo RJF, Braga TT, Davanzo GG, Gambarini V, Antonio T, Antiorio ATFB, Hiyane MI, Morais da Fonseca D, Andrade-Oliveira V, Câmara NOS. Fecal IgA Levels and Gut Microbiota Composition Are Regulated by Invariant Natural Killer T Cells. Inflamm Bowel Dis 2020; 26:697-708. [PMID: 31819985 DOI: 10.1093/ibd/izz300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The gut microbiota is a key element to support host homeostasis and the development of the immune system. The relationship between the microbiota and immunity is a 2-way road, in which the microbiota contributes to the development/function of immune cells and immunity can affect the composition of microbes. In this context, natural killer T cells (NKT cells) are distinct T lymphocytes that play a role in gut immunity and are influenced by gut microbes. In our work, we investigated the involvement of invariant NKT cells (iNKT) in intestinal homeostasis. RESULTS We found that iNKT-deficient mice (iNKT-KO) had reduced levels of fecal IgA and an altered composition of the gut microbiota, with increased Bacteroidetes. The absence of iNKT cells also affected TGF-β1 levels and plasma cells, which were significantly reduced in knockout (KO) mice. In addition, when submitted to dextran sodium sulfate colitis, iNKT-KO mice had worsening of colitis when compared with wild-type (WT) mice. To further address iNKT cell contribution to intestinal homeostasis, we adoptively transferred iNKT cells to KO mice, and they were submitted to colitis. Transfer of iNKT cells improved colitis and restored fecal IgA levels and gut microbiota. CONCLUSIONS Our results indicate that intestinal NKT cells are important modulators of intestinal homeostasis and that gut microbiota composition may be a potential target in the management of inflammatory bowel diseases.
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Affiliation(s)
- Cristhiane Favero de Aguiar
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.,Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Angela Castoldi
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Mariane T Amano
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.,Instituto Sírio-Libanês de Ensino e Pesquisa, Hospital Sírio-Libanês, São Paulo-SP, Brazil
| | - Aline Ignacio
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Fernanda Fernandes Terra
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Mario Cruz
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Raphael J F Felizardo
- Division of Nephrology, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo-SP, Brazil
| | - Tárcio Teodoro Braga
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Gustavo Gastão Davanzo
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Victor Gambarini
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Tiago Antonio
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Ana Tada Fonseca Brasil Antiorio
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Meire Ioshie Hiyane
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Denise Morais da Fonseca
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Vinicius Andrade-Oliveira
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.,Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), Santo André-SP, Brazil
| | - Niels Olsen Saraiva Câmara
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.,Division of Nephrology, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo-SP, Brazil
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33
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Gao YL, Shao LH, Dong LH, Chang PY. Gut commensal bacteria, Paneth cells and their relations to radiation enteropathy. World J Stem Cells 2020; 12:188-202. [PMID: 32266051 PMCID: PMC7118286 DOI: 10.4252/wjsc.v12.i3.188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/12/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent self-renewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein, the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.
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Affiliation(s)
- Yan-Li Gao
- Department of Pediatric Ultrasound, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Hong Shao
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Hua Dong
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Peng-Yu Chang
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China.
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34
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Crowe J, Lumb FE, Doonan J, Broussard M, Tarafdar A, Pineda MA, Landabaso C, Mulvey L, Hoskisson PA, Babayan SA, Selman C, Harnett W, Harnett MM. The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing. PLoS Pathog 2020; 16:e1008391. [PMID: 32163524 PMCID: PMC7108737 DOI: 10.1371/journal.ppat.1008391] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 03/31/2020] [Accepted: 02/07/2020] [Indexed: 12/15/2022] Open
Abstract
Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 μg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals.
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Affiliation(s)
- Jenny Crowe
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Felicity E. Lumb
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - James Doonan
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - Margaux Broussard
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Anuradha Tarafdar
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Miguel A. Pineda
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Carmen Landabaso
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Lorna Mulvey
- Glasgow Ageing Research Network (GARNER), Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
| | - Paul A. Hoskisson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - Simon A. Babayan
- Glasgow Ageing Research Network (GARNER), Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
| | - Colin Selman
- Glasgow Ageing Research Network (GARNER), Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
| | - William Harnett
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - Margaret M. Harnett
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
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Brailey PM, Lebrusant‐Fernandez M, Barral P. NKT cells and the regulation of intestinal immunity: a two‐way street. FEBS J 2020; 287:1686-1699. [PMID: 32022989 DOI: 10.1111/febs.15238] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/17/2020] [Accepted: 02/03/2020] [Indexed: 12/14/2022]
Abstract
The mammalian gastrointestinal compartment is colonised by millions of microorganisms that have a central influence on human health. Intestinal homeostasis requires a continuous dialogue between the commensal bacteria and intestinal immune cells. While interactions between host and commensal bacteria are normally beneficial, allowing training and functional tuning of immune cells, dysregulated immune system-microbiota crosstalk can favour the development of chronic inflammatory diseases, as it is the case for inflammatory bowel disease (IBD). Natural killer T (NKT) cells, which recognise CD1-restricted microbial and self-lipids, contribute to the regulation of mucosal immunity by controlling intestinal homeostasis and participating in the development of IBD. Here, we provide an overview of the recently identified pathways underlying the crosstalk between commensal bacteria and NKT cells and discuss the effect of these interactions in intestinal health and disease.
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Affiliation(s)
- Phillip M. Brailey
- The Peter Gorer Department of Immunobiology King’s College London UK
- The Francis Crick Institute London UK
| | - Marta Lebrusant‐Fernandez
- The Peter Gorer Department of Immunobiology King’s College London UK
- The Francis Crick Institute London UK
| | - Patricia Barral
- The Peter Gorer Department of Immunobiology King’s College London UK
- The Francis Crick Institute London UK
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Riffelmacher T, Kronenberg M. Metabolic Triggers of Invariant Natural Killer T-Cell Activation during Sterile Autoinflammatory Disease. Crit Rev Immunol 2020; 40:367-378. [PMID: 33463949 PMCID: PMC7116673 DOI: 10.1615/critrevimmunol.2020035158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ample evidence exists for activation of invariant natural killer T (iNKT) cells in a sterile manner by endogenous ligands or microbial antigens from the commensal flora, indicating that iNKT cells are not truly self-tolerant. Their controlled autoreactivity state is disturbed in many types of sterile inflammatory disease, resulting in their central role in modulating autoimmune responses. This review focuses on sterile iNKT-cell responses that are initiated by metabolic triggers, such as obesity-associated inflammation and fatty liver disease, as a manifestation of metabolic disease and dyslipidemia, as well as ischemia reperfusion injuries and sickle cell disease, characterized by acute lack of oxygen and oxidative stress response on reperfusion. In the intestine, inflammation and iNKT-cell response type are shaped by the microbiome as an extended "self". Disease- and organ-specific differences in iNKT-cell response type are summarized and help to define common pathways that shape iNKT-cell responses in the absence of exogenous antigen.
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Affiliation(s)
- Thomas Riffelmacher
- La Jolla Institute for Immunology, La Jolla, CA 92037
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Mitchell Kronenberg
- La Jolla Institute for Immunology, La Jolla, CA 92037
- Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093
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Yang D, Xing Y, Song X, Qian Y. The impact of lung microbiota dysbiosis on inflammation. Immunology 2019; 159:156-166. [PMID: 31631335 DOI: 10.1111/imm.13139] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 10/05/2019] [Accepted: 10/15/2019] [Indexed: 12/11/2022] Open
Abstract
Host-microbiota interaction plays fundamental roles in the homeostasis of mucosal immunity. Dysbiosis of intestinal microbiota has been demonstrated to participate in various immune responses and many multifactorial diseases. Study of intestinal microbiota has moved beyond the consequences of dysbiosis to the causal microbiota associated with diseases. However, studies of pulmonary microbiota and its dysbiosis are still in their infancy. Improvement of culture-dependent and -independent techniques has facilitated our understanding of lung microbiota that not only exists in healthy lung tissue but also exerts great impact on immune responses under both physiological and pathological conditions. In this review, we summarize recent progresses of lung microbiota dysbiosis and its impact on the local immune system that determines the balance of tolerance and inflammation. We discuss the causal roles of pulmonary dysbiosis under disease settings, and propose that the interaction between lung microbiota and host is critical for establishing the immune homeostasis in lung.
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Affiliation(s)
- Daping Yang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yingying Xing
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xinyang Song
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Youcun Qian
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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VanderLaan PA, Reardon CA, Cabana VG, Wang CR, Getz GS. Invariant Natural Killer T-Cells and Total CD1d Restricted Cells Differentially Influence Lipid Metabolism and Atherosclerosis in Low Density Receptor Deficient Mice. Int J Mol Sci 2019; 20:ijms20184566. [PMID: 31540125 PMCID: PMC6770011 DOI: 10.3390/ijms20184566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/05/2019] [Accepted: 09/11/2019] [Indexed: 11/16/2022] Open
Abstract
Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR−/−) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in Jα18−/−LDLR−/− mice led to an increase in plasma cholesterol levels in female mice. Transgenic Vα14tg/LDLR−/− mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells.
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Affiliation(s)
- Paul A VanderLaan
- Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
| | | | | | - Chyung-Ru Wang
- Department of Microbiology and Immunology, Northwestern University, 633 Clark St, Evanston, IL 60208, USA.
| | - Godfrey S Getz
- Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
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Abstract
Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) α-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (TH1), TH2 and TH17 cell subsets. Additional iNKT cell subsets that may require peripheral activation have also been described, including one that produces IL-10. In general, iNKT cells are non-circulating, tissue-resident lymphocytes, but the prevalence of different iNKT cell subsets differs markedly between tissues. Here, we summarize the functions of iNKT cells in four tissues in which they are prevalent, namely, the liver, the lungs, adipose tissue and the intestine. Importantly, we explain how local iNKT cell responses at each site contribute to tissue homeostasis and protection from infection but can also contribute to tissue inflammation and damage.
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40
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Lee C, Hong SN, Paik NY, Kim TJ, Kim ER, Chang DK, Kim YH. CD1d Modulates Colonic Inflammation in NOD2-/- Mice by Altering the Intestinal Microbial Composition Comprising Acetatifactor muris. J Crohns Colitis 2019; 13:1081-1091. [PMID: 31094420 DOI: 10.1093/ecco-jcc/jjz025] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AIMS NOD2 and CD1d play a key role in innate immunity by recognizing conserved molecular patterns of pathogens. While NOD2-/- and CD1d-/- mice display structural and functional alterations in Paneth cells, animal studies have reported no impact of NOD2 or CD1d deficiency on experimental colitis. NOD2 mutations increase the susceptibility to inflammatory bowel diseases and the CD1d bound to α-galactosylceramide [α-GalCer] alleviates intestinal inflammation. We evaluated the effect of CD1d modulation on experimental colitis in NOD2-/- mice. METHODS The effect of CD1d augmentation and depletion in NOD2-/- mice was assessed in a dextran sodium sulphate [DSS]-induced colitis model via administration of α-GalCer and construction of NOD2-/-CD1d-/- mice. The structural and functional changes in Paneth cells were evaluated using transmission electron microscopy and pilocarpine administration. Colitogenic taxa were analysed in the faeces of NOD2-/-CD1d-/- mice using 16S rRNA gene sequencing. RESULTS In NOD2-/- mice, α-GalCer alleviated and CD1d depletion [NOD2-/-CD1d-/- mice] aggravated colitis activity and histology compared with co-housed littermates NOD2-/-, CD1d-/- and wild-type mice after administration of 3% DSS. In NOD2-/-CD1d-/- mice, the ultrastructure and degranulation ability of secretary granules in Paneth cells were altered and the intestinal microbial composition differed from that of their littermates. Faecal microbiota transplantation [FMT] with NOD2-/-CD1d-/- mice faeces into wild-type mice aggravated DSS-induced colitis, while FMT with wild-type mice faeces into NOD2-/-CD1d-/- mice alleviated DSS-induced colitis. Acetatifactor muris was identified only in NOD2-/-CD1d-/- mice faeces and the oral gavage of A. muris in wild-type mice aggravated DSS-induced colitis. CONCLUSION CD1d modulates colonic inflammation in NOD2-/- mice by altering the intestinal microbial composition comprising A. muris.
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Affiliation(s)
- Chansu Lee
- Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Nam Young Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Jun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Kyung Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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41
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Clancy‐Thompson E, Chen GZ, LaMarche NM, Ali LR, Jeong H, Crowley SJ, Boelaars K, Brenner MB, Lynch L, Dougan SK. Transnuclear mice reveal Peyer's patch iNKT cells that regulate B-cell class switching to IgG1. EMBO J 2019; 38:e101260. [PMID: 31304630 PMCID: PMC6627243 DOI: 10.15252/embj.2018101260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/28/2019] [Accepted: 05/02/2019] [Indexed: 12/27/2022] Open
Abstract
Tissue-resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T-bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild-type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin-draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP-NKT cells produce the majority of the IL-4 in Peyer's patches and provide indirect help for B-cell class switching to IgG1 in both transnuclear and wild-type mice. Oral vaccination with α-galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell-sufficient mice. Transcriptional profiling reveals a unique signature of PP-NKT cells, characterized by tissue residency. We thus define PP-NKT as potentially important for surveillance for mucosal pathogens.
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Affiliation(s)
| | - Gui Zhen Chen
- Department of Cancer Immunology and VirologyDana‐Farber Cancer InstituteBostonMAUSA
| | - Nelson M LaMarche
- Department of RheumatologyBrigham and Women's HospitalBostonMAUSA
- Program in ImmunologyHarvard Medical SchoolBostonMAUSA
| | - Lestat R Ali
- Department of Cancer Immunology and VirologyDana‐Farber Cancer InstituteBostonMAUSA
| | - Hee‐Jin Jeong
- Department of Cancer Immunology and VirologyDana‐Farber Cancer InstituteBostonMAUSA
- Present address:
Hongik UniversitySeoulKorea
| | - Stephanie J Crowley
- Department of Cancer Immunology and VirologyDana‐Farber Cancer InstituteBostonMAUSA
| | - Kelly Boelaars
- Department of Cancer Immunology and VirologyDana‐Farber Cancer InstituteBostonMAUSA
- VU University AmsterdamAmsterdamThe Netherlands
| | - Michael B Brenner
- Department of RheumatologyBrigham and Women's HospitalBostonMAUSA
- Program in ImmunologyHarvard Medical SchoolBostonMAUSA
| | - Lydia Lynch
- Department of RheumatologyBrigham and Women's HospitalBostonMAUSA
- Program in ImmunologyHarvard Medical SchoolBostonMAUSA
| | - Stephanie K Dougan
- Department of Cancer Immunology and VirologyDana‐Farber Cancer InstituteBostonMAUSA
- Program in ImmunologyHarvard Medical SchoolBostonMAUSA
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Srugo SA, Bloise E, Nguyen TTTN, Connor KL. Impact of Maternal Malnutrition on Gut Barrier Defense: Implications for Pregnancy Health and Fetal Development. Nutrients 2019; 11:nu11061375. [PMID: 31248104 PMCID: PMC6628366 DOI: 10.3390/nu11061375] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 05/31/2019] [Accepted: 06/10/2019] [Indexed: 12/16/2022] Open
Abstract
Small intestinal Paneth cells, enteric glial cells (EGC), and goblet cells maintain gut mucosal integrity, homeostasis, and influence host physiology locally and through the gut-brain axis. Little is known about their roles during pregnancy, or how maternal malnutrition impacts these cells and their development. Pregnant mice were fed a control diet (CON), undernourished by 30% vs. control (UN), or fed a high fat diet (HF). At day 18.5 (term = 19), gut integrity and function were assessed by immunohistochemistry and qPCR. UN mothers displayed reduced mRNA expression of Paneth cell antimicrobial peptides (AMP; Lyz2, Reg3g) and an accumulation of villi goblet cells, while HF had reduced Reg3g and mucin (Muc2) mRNA and increased lysozyme protein. UN fetuses had increased mRNA expression of gut transcription factor Sox9, associated with reduced expression of maturation markers (Cdx2, Muc2), and increased expression of tight junctions (TJ; Cldn-7). HF fetuses had increased mRNA expression of EGC markers (S100b, Bfabp, Plp1), AMP (Lyz1, Defa1, Reg3g), and TJ (Cldn-3, Cldn-7), and reduced expression of an AMP-activator (Tlr4). Maternal malnutrition altered expression of genes that maintain maternal gut homeostasis, and altered fetal gut permeability, function, and development. This may have long-term implications for host-microbe interactions, immunity, and offspring gut-brain axis function.
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Affiliation(s)
- Sebastian A Srugo
- Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada.
| | - Enrrico Bloise
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil.
| | | | - Kristin L Connor
- Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada.
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
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Burrello C, Giuffrè MR, Macandog AD, Diaz-Basabe A, Cribiù FM, Lopez G, Borgo F, Nezi L, Caprioli F, Vecchi M, Facciotti F. Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition. Cells 2019; 8:E517. [PMID: 31142049 PMCID: PMC6628315 DOI: 10.3390/cells8060517] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 02/06/2023] Open
Abstract
Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.
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Affiliation(s)
- Claudia Burrello
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy; (C.B.); (A.D.M.); (A.D.-B.); (F.B.); (L.N.)
| | - Maria Rita Giuffrè
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20135 Milan, Italy; mariarita.giuffre’@ieo.it (M.R.G.); (F.C.); (M.V.)
| | - Angeli Dominique Macandog
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy; (C.B.); (A.D.M.); (A.D.-B.); (F.B.); (L.N.)
- Department of Oncology and Hemato-oncology, Università degli Studi di Milano, 20135 Milan, Italy
| | - Angelica Diaz-Basabe
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy; (C.B.); (A.D.M.); (A.D.-B.); (F.B.); (L.N.)
| | - Fulvia Milena Cribiù
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, 20135 Milan, Italy; (F.M.C.); (G.L.)
| | - Gianluca Lopez
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, 20135 Milan, Italy; (F.M.C.); (G.L.)
| | - Francesca Borgo
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy; (C.B.); (A.D.M.); (A.D.-B.); (F.B.); (L.N.)
| | - Luigi Nezi
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy; (C.B.); (A.D.M.); (A.D.-B.); (F.B.); (L.N.)
| | - Flavio Caprioli
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20135 Milan, Italy; mariarita.giuffre’@ieo.it (M.R.G.); (F.C.); (M.V.)
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Maurizio Vecchi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20135 Milan, Italy; mariarita.giuffre’@ieo.it (M.R.G.); (F.C.); (M.V.)
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy; (C.B.); (A.D.M.); (A.D.-B.); (F.B.); (L.N.)
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Cheng HY, Ning MX, Chen DK, Ma WT. Interactions Between the Gut Microbiota and the Host Innate Immune Response Against Pathogens. Front Immunol 2019; 10:607. [PMID: 30984184 PMCID: PMC6449424 DOI: 10.3389/fimmu.2019.00607] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/07/2019] [Indexed: 12/12/2022] Open
Abstract
The mammalian intestine is colonized by over a trillion microbes that comprise the "gut microbiota," a microbial community which has co-evolved with the host to form a mutually beneficial relationship. Accumulating evidence indicates that the gut microbiota participates in immune system maturation and also plays a central role in host defense against pathogens. Here we review some of the mechanisms employed by the gut microbiota to boost the innate immune response against pathogens present on epithelial mucosal surfaces. Antimicrobial peptide secretion, inflammasome activation and induction of host IL-22, IL-17, and IL-10 production are the most commonly observed strategies employed by the gut microbiota for host anti-pathogen defense. Taken together, the body of evidence suggests that the host gut microbiota can elicit innate immunity against pathogens.
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Affiliation(s)
- Hong-Yu Cheng
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China
| | - Meng-Xia Ning
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China
| | - De-Kun Chen
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China
| | - Wen-Tao Ma
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China
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45
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Burrello C, Pellegrino G, Giuffrè MR, Lovati G, Magagna I, Bertocchi A, Cribiù FM, Boggio F, Botti F, Trombetta E, Porretti L, Di Sabatino A, Vecchi M, Rescigno M, Caprioli F, Facciotti F. Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells. Life Sci Alliance 2019; 2:2/1/e201800229. [PMID: 30760554 PMCID: PMC6374994 DOI: 10.26508/lsa.201800229] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/01/2019] [Accepted: 02/01/2019] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) pathogenesis has been linked to the aberrant activation of the Gut-associated lymphoid tissues against components of the intestinal microbiota. Although the contribution of CD4+ T helper cells to inflammatory processes is being increasingly acknowledged, the functional engagement of human invariant natural killer T (iNKT) cells is still poorly defined. Here, we evaluated the functional characteristics of intestinal iNKT cells during IBD pathogenesis and to exploit the role of mucosa-associated microbiota recognition in triggering iNKT cells' pro-inflammatory responses in vivo. Lamina propria iNKT cells, isolated from surgical specimens of active ulcerative colitis and Crohn's disease patients and non-IBD donors, were phenotypically and functionally analyzed ex vivo, and stable cell lines and clones were generated for in vitro functional assays. iNKT cells expressing a pro-inflammatory cytokine profile were enriched in the lamina propria of IBD patients, and their exposure to the mucosa-associated microbiota drives pro-inflammatory activation, inducing direct pathogenic activities against the epithelial barrier integrity. These observations suggest that iNKT cell pro-inflammatory functions may contribute to the fuelling of intestinal inflammation in IBD patients.
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Affiliation(s)
- Claudia Burrello
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Gabriella Pellegrino
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Maria Rita Giuffrè
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Lovati
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Ilaria Magagna
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Alice Bertocchi
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Fulvia Milena Cribiù
- Pathology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Boggio
- Pathology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fiorenzo Botti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.,General and Emergency Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Trombetta
- Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Porretti
- Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Maria Rescigno
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
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Burrello C, Garavaglia F, Cribiù FM, Ercoli G, Lopez G, Troisi J, Colucci A, Guglietta S, Carloni S, Guglielmetti S, Taverniti V, Nizzoli G, Bosari S, Caprioli F, Rescigno M, Facciotti F. Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat Commun 2018; 9:5184. [PMID: 30518790 PMCID: PMC6281577 DOI: 10.1038/s41467-018-07359-8] [Citation(s) in RCA: 210] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 10/25/2018] [Indexed: 12/12/2022] Open
Abstract
Alteration of the gut microbiota has been associated with different gastrointestinal disorders. Normobiosis restoration by faecal microbiota transplantation (FMT) is considered a promising therapeutic approach, even if the mechanisms underlying its efficacy are at present largely unknown. Here we sought to elucidate the functional effects of therapeutic FMT administration during experimental colitis on innate and adaptive immune responses in the intestinal mucosa. We show that therapeutic FMT reduces colonic inflammation and initiates the restoration of intestinal homeostasis through the simultaneous activation of different immune-mediated pathways, ultimately leading to IL-10 production by innate and adaptive immune cells, including CD4+ T cells, iNKT cells and Antigen Presenting Cells (APC), and reduces the ability of dendritic cells, monocytes and macrophages to present MHCII-dependent bacterial antigens to colonic T cells. These results demonstrate the capability of FMT to therapeutically control intestinal experimental colitis and poses FMT as a valuable therapeutic option in immune-related pathologies.
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Affiliation(s)
- Claudia Burrello
- Department of Experimental Oncology, European Institute of Oncology IRCCS, via Adamello 16, Milan, 20139, Italy.,Department of Oncology and Hemato-oncology, Università degli Studi di Milano, via F. Sforza 28, Milan, 20122, Italy
| | - Federica Garavaglia
- Department of Experimental Oncology, European Institute of Oncology IRCCS, via Adamello 16, Milan, 20139, Italy
| | - Fulvia Milena Cribiù
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20135, Italy
| | - Giulia Ercoli
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20135, Italy
| | - Gianluca Lopez
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20135, Italy
| | - Jacopo Troisi
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi, 84081, SA, Italy.,Theoreo srl, Spin-off company of the University of Salerno, Via degli Ulivi 3, 84090, Montecorvino Pugliano, SA, Italy.,European Biomedical Research Institute of Salerno (EBRIS), Via S. de Renzi, 3, 84125, Salerno, SA, Italy
| | - Angelo Colucci
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi, 84081, SA, Italy.,Theoreo srl, Spin-off company of the University of Salerno, Via degli Ulivi 3, 84090, Montecorvino Pugliano, SA, Italy
| | - Silvia Guglietta
- Department of Experimental Oncology, European Institute of Oncology IRCCS, via Adamello 16, Milan, 20139, Italy
| | - Sara Carloni
- Laboratory of Mucosal Immunology and Microbiota, Humanitas Clinical and Research Center, Via Manzoni 56, Milan, 20089, Italy
| | - Simone Guglielmetti
- Department of Food Environmental and Nutritional Sciences (DeFENS), Università degli Studi di Milano, Milan, 20133, via Celoria 2, Italy
| | - Valentina Taverniti
- Department of Food Environmental and Nutritional Sciences (DeFENS), Università degli Studi di Milano, Milan, 20133, via Celoria 2, Italy
| | - Giulia Nizzoli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20135, Italy
| | - Silvano Bosari
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20135, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20135, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via F. Sforza 28, Milan, 20135, Italy
| | - Maria Rescigno
- Laboratory of Mucosal Immunology and Microbiota, Humanitas Clinical and Research Center, Via Manzoni 56, Milan, 20089, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, European Institute of Oncology IRCCS, via Adamello 16, Milan, 20139, Italy.
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Marrero I, Maricic I, Feldstein AE, Loomba R, Schnabl B, Rivera-Nieves J, Eckmann L, Kumar V. Complex Network of NKT Cell Subsets Controls Immune Homeostasis in Liver and Gut. Front Immunol 2018; 9:2082. [PMID: 30254647 PMCID: PMC6141878 DOI: 10.3389/fimmu.2018.02082] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/22/2018] [Indexed: 12/23/2022] Open
Abstract
The liver-gut immune axis is enriched in several innate immune cells, including innate-like unconventional and adaptive T cells that are thought to be involved in the maintenance of tolerance to gut-derived antigens and, at the same time, enable effective immunity against microbes. Two subsets of lipid-reactive CD1d-restricted natural killer T (NKT) cells, invariant NKT (iNKT) and type II NKT cells present in both mice and humans. NKT cells play an important role in regulation of inflammation in the liver and gut due to their innate-like properties of rapid secretion of a myriad of pro-inflammatory and anti-inflammatory cytokines and their ability to influence other innate cells as well as adaptive T and B cells. Notably, a bi-directional interactive network between NKT cells and gut commensal microbiota plays a crucial role in this process. Here, we briefly review recent studies related to the cross-regulation of both NKT cell subsets and how their interactions with other immune cells and parenchymal cells, including hepatocytes and enterocytes, control inflammatory diseases in the liver, such as alcoholic and non-alcoholic steatohepatitis, as well as inflammation in the gut. Overwhelming experimental data suggest that while iNKT cells are pathogenic, type II NKT cells are protective in the liver. Since CD1d-dependent pathways are highly conserved from mice to humans, a detailed cellular and molecular understanding of these immune regulatory pathways will have major implications for the development of novel therapeutics against inflammatory diseases of liver and gut.
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Affiliation(s)
- Idania Marrero
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Igor Maricic
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Bernd Schnabl
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Jesus Rivera-Nieves
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Lars Eckmann
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Vipin Kumar
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
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48
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Hapil FZ, Wingender G. The interaction between invariant Natural Killer T cells and the mucosal microbiota. Immunology 2018; 155:164-175. [PMID: 29893412 DOI: 10.1111/imm.12958] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 05/21/2018] [Indexed: 02/06/2023] Open
Abstract
The surface of mammalian bodies is colonized by a multitude of microbial organisms, which under normal conditions support the host and are considered beneficial commensals. This requires, however, that the composition of the commensal microbiota is tightly controlled and regulated. The host immune system plays an important role in the maintenance of this microbiota composition. Here we focus on the contribution of one particular immune cell type, invariant Natural Killer T (iNKT) cells, in this process. The iNKT cells are a unique subset of T cells characterized by two main features. First, they express an invariant T-cell receptor that recognizes glycolipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like molecule. Second, iNKT cells develop as effector/memory cells and swiftly exert effector functions, like cytokine production and cytotoxicity, after activation. We outline the influence that the mucosal microbiota can have on iNKT cells, and how iNKT cells contribute to the maintenance of the microbiota composition.
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Affiliation(s)
| | - Gerhard Wingender
- Izmir Biomedicine and Genome Center, Balcova/Izmir, Turkey.,Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova/Izmir, Turkey
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49
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Satoh M, Iwabuchi K. Role of Natural Killer T Cells in the Development of Obesity and Insulin Resistance: Insights From Recent Progress. Front Immunol 2018; 9:1314. [PMID: 29942311 PMCID: PMC6004523 DOI: 10.3389/fimmu.2018.01314] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 05/28/2018] [Indexed: 12/22/2022] Open
Abstract
Natural killer T (NKT) cells play important roles in adipose tissue inflammation, and thus influence the development of diet-induced obesity and insulin resistance. The interactions between cluster of differentiation (CD)1d and NKT T cell receptor are thought to be critical in this process, as demonstrated in two NKT cell-deficient mouse models-systemic CD1d gene knockout (KO) and prototypic Jα18 KO mice. The latter lacks some repertoires besides invariant (i)NKT cells due to manipulation of the Jα18 gene segment; therefore, the role of iNKT vs. variant NKT cells must be reinterpreted considering the availability of new Jα18 KO mice. NKT cells have varied roles in the development of obesity; indeed, studies have reported contradictory results depending on the mouse model, diet, and rearing conditions, all of which could affect the microbiome. In this mini-review, we discuss these points considering recent findings from our laboratory and others as well as the role of NKT cells in the development of obesity and insulin resistance based on data obtained from studies on conditional CD1d1 KO and new Jα18 KO mice generated through gene editing.
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Affiliation(s)
- Masashi Satoh
- Department of Immunology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kazuya Iwabuchi
- Department of Immunology, Kitasato University School of Medicine, Sagamihara, Japan
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50
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Ververs FA, Kalkhoven E, Van't Land B, Boes M, Schipper HS. Immunometabolic Activation of Invariant Natural Killer T Cells. Front Immunol 2018; 9:1192. [PMID: 29892305 PMCID: PMC5985373 DOI: 10.3389/fimmu.2018.01192] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 05/14/2018] [Indexed: 12/23/2022] Open
Abstract
Invariant natural killer T (iNKT) cells are lipid-reactive T cells with profound immunomodulatory potential. They are unique in their restriction to lipid antigens presented in CD1d molecules, which underlies their role in lipid-driven disorders such as obesity and atherosclerosis. In this review, we discuss the contribution of iNKT cell activation to immunometabolic disease, metabolic programming of lipid antigen presentation, and immunometabolic activation of iNKT cells. First, we outline the role of iNKT cells in immunometabolic disease. Second, we discuss the effects of cellular metabolism on lipid antigen processing and presentation to iNKT cells. The synthesis and processing of glycolipids and other potential endogenous lipid antigens depends on metabolic demand and may steer iNKT cells toward adopting a Th1 or Th2 signature. Third, external signals such as toll-like receptor ligands, adipokines, and cytokines modulate antigen presentation and subsequent iNKT cell responses. Finally, we will discuss the relevance of metabolic programming of iNKT cells in human disease, focusing on their role in disorders such as obesity and atherosclerosis. The critical response to metabolic changes places iNKT cells at the helm of immunometabolic disease.
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Affiliation(s)
- Francesca A Ververs
- Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Eric Kalkhoven
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands
| | - Belinda Van't Land
- Department of Immunology, Nutricia Research, Utrecht, Netherlands.,Department of Pediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Marianne Boes
- Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.,Department of Pediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Henk S Schipper
- Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.,Department of Pediatric Cardiology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
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