Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function

Olszak, Torsten; An, Dingding; Zeißig, Sebastian; Vera, Miguel Pinilla; Richter, Julia; Franke, André; Glickman, Jonathan N.; Siebert, Reiner; Baron, Rebecca M.; Kasper, Dennis L.; Blumberg, Richard S.

doi:10.1126/science.1219328

Cited by 1,388 publications

(1,270 citation statements)

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“…It is possible that in early life during initiating events in the development of allergic and autoimmune disease, such conditions are associated with a skewing towards a type 2 cytokine‐secreting profile in MAIT cells, as occurs with other T‐cell subsets,44, 64 and may occur early in life. Exposure to microbes during early childhood is associated with protection from immune‐mediated diseases 76, 77, 78. One mechanism may be persistent effects on numbers and function of innate lymphocytes, such as the accumulation of iNKT cells, which occurs in the lamina propria and lungs of germ‐free mice, resulting in increased morbidity in models of inflammatory bowel disease and allergic airways inflammation 77, 79.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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SummaryMucosal‐associated invariant T (MAIT) cells are a novel class of innate‐like T cells, expressing a semi‐invariant T‐cell receptor (TCR) and able to recognize small molecules presented on the non‐polymorphic MHC‐related protein 1. Their intrinsic effector‐memory phenotype, enabling secretion of pro‐inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune‐mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation‐induced down‐regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR‐independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.

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Section: Observations From Specific Diseasesmentioning

confidence: 99%

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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“…However, one important factor is the regulation of the chemokine CXCL16, which is important for natural killer (iNK) T-cell migration and homeostasis. This chemokine regulation has been shown to occur through epigenetic changes involving the reduction of methylation pattern of the CXCl16 gene and in so doing reducing the number of invariant NK T cells in the colonic lamina propria (Olszak et al, 2012). Bacteroides fragilis (B. fragilis) provides another example of a factor critical for the normal function of the immune system by producing glycosphingolipid which in turn inhibits natural killer T cells proliferation in the colonic lamina propria (Wieland Brown et al, 2013).…”

Section: Microbes and Immunitymentioning

confidence: 99%

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

Dinan

Cryan

2016

Neuropsychopharmacol

183

110

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There is now a large volume of evidence to support the view that the immune system is a key communication pathway between the gut and brain, which plays an important role in stress-related psychopathologies and thus provides a potentially fruitful target for psychotropic intervention. The gut microbiota is a complex ecosystem with a diverse range of organisms and a sophisticated genomic structure. Bacteria within the gut are estimated to weigh in excess of 1 kg in the adult human and the microbes within not only produce antimicrobial peptides, short chain fatty acids, and vitamins, but also most of the common neurotransmitters found in the human brain. That the microbial content of the gut plays a key role in immune development is now beyond doubt. Early disruption of the host-microbe interplay can have lifelong consequences, not just in terms of intestinal function but in distal organs including the brain. It is clear that the immune system and nervous system are in continuous communication in order to maintain a state of homeostasis. Significant gaps in knowledge remain about the effect of the gut microbiota in coordinating the immune-nervous systems dialogue. However, studies using germ-free animals, infective models, prebiotics, probiotics, and antibiotics have increased our understanding of the interplay. Early life stress can have a lifelong impact on the microbial content of the intestine and permanently alter immune functioning. That early life stress can also impact adult psychopathology has long been appreciated in psychiatry. The challenge now is to fully decipher the molecular mechanisms that link the gut microbiota, immune, and central nervous systems in a network of communication that impacts behavior patterns and psychopathology, to eventually translate these findings to the human situation both in health and disease. Even at this juncture, there is evidence to pinpoint key sites of communication where gut microbial interventions either with drugs or diet or perhaps fecal microbiota transplantation may positively impact mental health.

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“…These cells patrol the murine liver sinusoids where they represent ∼20% of resident lymphocytes and can release proinflammatory cytokines (2,3). iNKT cells recognize glycolipid Ags presented by the nonpolymorphic CD1d molecule (4) and play an important role in the pathogenesis with different etiologies (5)(6)(7)(8). However, in humans, the identity of intrahepatic T cells expressing NK markers is controversial (1,2,9).…”

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confidence: 99%

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Tang

Tan

et al. 2013

The Journal of Immunology

301

393

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Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A+ T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.

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Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function

Cited by 1,388 publications

References 39 publications

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

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