Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

Fuss, Ivan J.; Heller, Frank; Boirivant, Monica; León, Francisco; Yoshida, Masaru; Fichtner‐Feigl, Stefan; Yang, Zhaopeng; Exley, Mark A.; Kitani, Atsushi; Blumberg, Richard S.; Mannon, Peter J.; Strober, Warren

doi:10.1172/jci19836

Cited by 680 publications

(370 citation statements)

References 49 publications

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“…This pathway could have implications for a variety of immune responses where CD1d‐dependent immunity plays a central role 10, 11. For instance, CD1d contributes to the functional regulation of immune cells in a variety of autoimmune disorders (such as IBD or systemic lupus erythematosus) consequently shaping the initiation and/or progression of the immune response 42, 43, 44, 45. Accordingly, CD1d expression is down‐regulated on IECs from patients with IBD and on B cells from patients with systemic lupus erythematosus, which correlates with abnormal function of IECs, B cells and NKT cells in these diseases.…”

Section: Resultsmentioning

confidence: 99%

CD 1d‐mediated activation of group 3 innate lymphoid cells drives IL ‐22 production

et al. 2016

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Innate lymphoid cells (ILCs) are a heterogeneous family of immune cells that play a critical role in a variety of immune processes including host defence against infection, wound healing and tissue repair. Whether these cells are involved in lipid‐dependent immunity remains unexplored. Here we show that murine ILCs from a variety of tissues express the lipid‐presenting molecule CD1d, with group 3 ILCs (ILC3s) showing the highest level of expression. Within the ILC3 family, natural cytotoxicity triggering receptor (NCR)− CCR6+ cells displayed the highest levels of CD1d. Expression of CD1d on ILCs is functionally relevant as ILC3s can acquire lipids in vitro and in vivo and load lipids on CD1d to mediate presentation to the T‐cell receptor of invariant natural killer T (iNKT) cells. Conversely, engagement of CD1d in vitro and administration of lipid antigen in vivo induce ILC3 activation and production of IL‐22. Taken together, our data expose a previously unappreciated role for ILCs in CD1d‐mediated immunity, which can modulate tissue homeostasis and inflammatory responses.

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Section: Resultsmentioning

confidence: 99%

CD 1d‐mediated activation of group 3 innate lymphoid cells drives IL ‐22 production

et al. 2016

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“…Ulcerative colitis is likely to involve similar mechanisms, but also Th2 cells secreting IL‐5 and IL‐13 and CD1d‐restricted type II NKT cells 52, 53. As with SLE, RhA and MS, in cross‐sectional observational studies there is a deficiency of human MAIT cells in peripheral blood in both Crohn's disease and ulcerative colitis,29, 54 although at least some of this effect is likely to be attributable to current or recent use of therapeutic corticosteroids, whether topical or systemic 55.…”

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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“…Despite the abundance of pro-and anti-inflammatory cytokines, such as IL-12, TNF-␣, IL-1␤, IL-16, and transforming growth factor ␤ (TGF-␤), that can be found in UC patients (234,237,(239)(240)(241), UC has traditionally been considered a CD4 ϩ T helper cell type 2 (Th2) disease (242,243). This view stemmed from the observation that increased levels of Th2-associated cytokines, including IL-5 and IL-13, can be measured in UC patients and experimental colitis models (239,243,244). Th2-associated cytokines have been shown in some studies to induce damaging effects at the mucosa.…”

Section: Ulcerative Colitis Pathophysiologymentioning

confidence: 99%

“…Th2-associated cytokines have been shown in some studies to induce damaging effects at the mucosa. IL-13, for example, is thought to mediate epithelial cell cytotoxicity, apoptosis, and barrier dysfunction in some situations (239,245). However, the importance of Th2 cytokines in UC pathogenesis relative to other cytokine pathways is currently unclear.…”

Section: Ulcerative Colitis Pathophysiologymentioning

confidence: 99%

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

et al. 2017

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SUMMARY Beneficial microorganisms hold promise for the treatment of numerous gastrointestinal diseases. The transfer of whole microbiota via fecal transplantation has already been shown to ameliorate the severity of diseases such as Clostridium difficile infection, inflammatory bowel disease, and others. However, the exact mechanisms of fecal microbiota transplant efficacy and the particular strains conferring this benefit are still unclear. Rationally designed combinations of microbial preparations may enable more efficient and effective treatment approaches tailored to particular diseases. Here we use an infectious disease, C. difficile infection, and an inflammatory disorder, the inflammatory bowel disease ulcerative colitis, as examples to facilitate the discussion of how microbial therapy might be rationally designed for specific gastrointestinal diseases. Fecal microbiota transplantation has already shown some efficacy in the treatment of both these disorders; detailed comparisons of studies evaluating commensal and probiotic organisms in the context of these disparate gastrointestinal diseases may shed light on potential protective mechanisms and elucidate how future microbial therapies can be tailored to particular diseases.

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Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

Abstract: While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its

Cited by 680 publications

References 49 publications

CD 1d‐mediated activation of group 3 innate lymphoid cells drives IL ‐22 production

CD 1d‐mediated activation of group 3 innate lymphoid cells drives IL ‐22 production

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

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

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