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MAIT Cells: A Link between Gut Integrity and Type 1 Diabetes

2017; Cell Press; Volume: 26; Issue: 6 Linguagem: Inglês

10.1016/j.cmet.2017.11.007

1932-7420

Elke Gülden, Noah W. Palm, Kevan C. Herold,

IL-33, ST2, and ILC Pathways

Type 1 diabetes (T1D) is a multifactorial autoimmune disease whose etiology involves complex interactions between the immune system and the intestinal microbiota. Recent studies by Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar suggest that innate-like mucosal-associated invariant T cells (MAIT cells) may link gut integrity, the microbiota, and T1D. Type 1 diabetes (T1D) is a multifactorial autoimmune disease whose etiology involves complex interactions between the immune system and the intestinal microbiota. Recent studies by Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar suggest that innate-like mucosal-associated invariant T cells (MAIT cells) may link gut integrity, the microbiota, and T1D. Type 1 diabetes (T1D) is a multifactorial autoimmune disease that results from T-cell-mediated destruction of insulin-producing β cells in the islets of Langerhans. Studies of the natural history of T1D have shown that individuals with two or more autoantibodies have initiated a pathologic immune response that will eventually lead to T1D, but the parameters and kinetics of this outcome are unclear, and environmental factors are likely to be important modifiers. Several lines of evidence suggest a key role for innate immune cells in disease initiation, progression, and even prevention. The intestinal microbiome is also altered prior to disease onset, and differences in the intrinsic immunogenicity of commensal endotoxins can modify T1D in non-obese diabetic (NOD) mice and humans (Vatanen et al., 2016Vatanen T. Kostic A.D. d'Hennezel E. Siljander H. Franzosa E.A. Yassour M. Kolde R. Vlamakis H. Arthur T.D. Hämäläinen A.M. et al.DIABIMMUNE Study GroupCell. 2016; 165: 1551Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). The link between observational studies and pathologic outcomes is difficult to address due to the heterogeneity of T1D patients and inaccessibility of key tissues. Recent studies by Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar add to this complexity by exposing a role for mucosal-associated invariant T cells (MAIT cells) in both T1D prevention and progression. MAIT cells are a recently identified class of innate-like lymphocytes with important roles in microbial defense. Like invariant natural killer (iNKT) cells, MAIT cells exhibit restricted T cell receptor (TCR) diversity. They are abundant in blood, liver, and mucosal tissues but absent in germ-free mice (Treiner et al., 2003Treiner E. Duban L. Bahram S. Radosavljevic M. Wanner V. Tilloy F. Affaticati P. Gilfillan S. Lantz O. Nature. 2003; 422: 164-169Crossref PubMed Scopus (766) Google Scholar). However, MAIT cells are rapidly restored following bacterial colonization, which suggests that they depend on the gut microbiota for their development and/or maintenance (Le Bourhis et al., 2010Le Bourhis L. Martin E. Péguillet I. Guihot A. Froux N. Coré M. Lévy E. Dusseaux M. Meyssonnier V. Premel V. et al.Nat. Immunol. 2010; 11: 701-708Crossref PubMed Scopus (648) Google Scholar). MAIT cells recognize bacterial metabolites derived from the biosynthesis of riboflavin, presented on the MHC I-related molecule (MR1) by antigen-presenting cells (APCs) (Keller et al., 2017Keller A.N. Corbett A.J. Wubben J.M. McCluskey J. Rossjohn J. Curr. Opin. Immunol. 2017; 46: 66-74Crossref PubMed Scopus (51) Google Scholar). Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar suggest that MAIT cells may play a direct role in β cell killing in humans with T1D and in NOD mice. The frequency of MAIT cells is reduced in the peripheral blood of children with recent onset T1D, but not established disease, as compared to control children. Also, they observe increased expression of CD25 and PD-1 by MAIT cells in T1D patients, which may reflect their increased activation status and migration to inflamed tissues (i.e., islets of Langerhans)—a suggestion supported by studies in the NOD mouse model of T1D. They find that an aggressive phenotype of MAIT cells in humans (increased TNF and granzyme B expression) is inversely correlated with age in new onset patients, possibly reflecting the more aggressive course of disease seen in young patients. Importantly, they found that MAIT cells could directly kill human pancreatic β cells (EndoC-β1) in vitro. These data argue for direct participation of MAIT cells in pancreatic β cell killing and in promotion of the destructive autoimmune choreography that ultimately results in T1D. They also propose that relative expression of the surface markers CCR6, CD25, PD-1, and CD56 on MAIT cells can serve as a biomarker of T1D susceptibility and progression: a suggestion that warrants further testing in relatives at risk for disease. In addition to their pathogenic role, Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar identify a protective role of MAIT cells in T1D development. Indeed, Mr1-deficient mice, which lack MAIT cells, exhibit increased rates of diabetes in mouse models of T1D, increased frequencies of diabetogenic IGRP-reactive CD8+ T cells, and decreased expression of occludin and mucin2 in intestinal epithelial cells. Thus, their data suggest that MAIT cells can enhance intestinal barrier function through the production of IL17A and IL-22 before the onset of T1D but that this protective role wanes during disease progression and may eventually transition to a pathogenic rather than protective role. What precipitates this change in MAIT cell phenotype remains unclear, but it is attractive to imagine that signals from the indigenous microbial community in the gut may play a crucial role. Is there a priority of protective and pathologic responses by these cells that goes awry in T1D? Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar suggest that MAIT cells play an important role in maintaining intestinal homeostasis and respond to alterations in the gut microbiota by altering overall immunological tone. In Mr1−/− mice, the mucosal barrier is compromised, and CD11b+CD11c+CD103+ dendritic cells (DCs) in the pancreatic lymph nodes, key for priming the diabetogenic response, are activated. Our recent observations in humanized mice support the role of these DCs as sensors of the intestinal environment (Gülden et al., 2017Gülden E. Vudattu N.K. Deng S. Preston-Hurlburt P. Mamula M. Reed J.C. Mohandas S. Herold B.C. Torres R. Vieira S.M. et al.JCI Insight. 2017; 2: 91709Crossref PubMed Scopus (16) Google Scholar). Since MAIT cells recognize bacterial metabolites presented by DCs via MR1, DCs form a crucial link between the gut microbiota and activation of the adaptive immune cells (Figure 1). Under homeostatic conditions, CD11b+CD11c+DCs may present bacterial metabolites to MAIT cells that exert protective roles in the gut through secretion of IL17A and IL22 and enhancement of the intestinal mucosal barrier. In dysbiotic conditions and/or in the setting of increased gut permeability, CD11b+CD11c+ DCs may present bacterial metabolites in the context of accompanying inflammatory signals that program these cells to reduce secretion of IL17A and IL22 but increase granzyme B and potentially contribute to pancreatic β cell killing. Consistent with this model, NF-κB signaling in APCs and proinflammatory cytokines are required for MR1-mediated MAIT cell activation to TCR stimulation (Ussher et al., 2016Ussher J.E. van Wilgenburg B. Hannaway R.F. Ruustal K. Phalora P. Kurioka A. Hansen T.H. Willberg C.B. Phillips R.E. Klenerman P. Eur. J. Immunol. 2016; 46: 1600-1614Crossref PubMed Scopus (83) Google Scholar, Turtle et al., 2011Turtle C.J. Delrow J. Joslyn R.C. Swanson H.M. Basom R. Tabellini L. Delaney C. Heimfeld S. Hansen J.A. Riddell S.R. Blood. 2011; 118: 2752-2762Crossref PubMed Scopus (88) Google Scholar). To translate these findings to the clinic, it will be important to determine whether changes in the microbiome in T1D are a cause or consequence of MAIT cell alterations and whether specific microbial species or strains are responsible for shaping MAIT cell functions. Rouxel et al., 2017Rouxel O. Da Silva J. Beaudoin L. Nel I. Tard C. Cagninacci L. Kiaf B. Oshima M. Diedisheim M. Salou M. et al.Nat. Immunol. 2017; 18: 1321-1331Crossref PubMed Scopus (147) Google Scholar did not observe any reductions in MAIT cell ligands in pellets from NOD mice at different ages, but whether targeted modification of the microbiome can change MAIT cell activity and affect gut permeability is untested. These findings raise the possibility that targeting MAIT cells for elimination or egress from the islets could ameliorate disease. However, experience from clinical trials would suggest that eliminating effector cells is not sufficient to reverse the disease permanently. Instead, these new findings suggest that triggering MAIT cells at the gut mucosa to enhance intestinal barrier function might be an effective strategy for prevention.