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Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes

A Correction to this article was published on 07 June 2018

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic β-cells by the immune system that involves innate and adaptive immune cells. Mucosal-associated invariant T cells (MAIT cells) are innate-like T-cells that recognize derivatives of precursors of bacterial riboflavin presented by the major histocompatibility complex (MHC) class I–related molecule MR1. Since T1D is associated with modification of the gut microbiota, we investigated MAIT cells in this pathology. In patients with T1D and mice of the non-obese diabetic (NOD) strain, we detected alterations in MAIT cells, including increased production of granzyme B, which occurred before the onset of diabetes. Analysis of NOD mice that were deficient in MR1, and therefore lacked MAIT cells, revealed a loss of gut integrity and increased anti-islet responses associated with exacerbated diabetes. Together our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. Monitoring of MAIT cells might represent a new biomarker of T1D, while manipulation of these cells might open new therapeutic strategies.

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Figure 1: Frequency and phenotype alterations of blood MAIT cells from T1D children.
Figure 2: Functional alterations of blood MAIT cells from T1D children.
Figure 3: Cytotoxic effect of MAIT cells on a human β-cell line.
Figure 4: MAIT-cell characteristics in patients at different disease stages.
Figure 5: Characterization of MAIT cells in NOD and C57BL/6 mice.
Figure 6: Frequency and function of MAIT cells during diabetes development.
Figure 7: Alterations to the gut mucosa during T1D progression in NOD mice.
Figure 8: MAIT-cell deficiency exacerbates the development of diabetes and alters the integrity of the gut mucosa.

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Acknowledgements

We thank all the patients and the medical staff of Necker hospital; A. Toubal for critical reading of the manuscript; F. Letourneur and A. Stabilini for technical help; the mouse, Cybio and HistIM facilities of the Cochin Institute; G, Eberl (Institut Pasteur, Paris) for the bacterial artificial chromosome expressing RORγt-GFP; the US National Institutes of Health tetramer core facility; and H. Fohrer-Ting, R. Porcher and M. Laanani for help in statistical analyses. Supported by the Société Francophone de Diabétologie (R.S.), the Foundation Bettencourt Schueller (R.S.), the Laboratoire d'Excellence REVIVE (R.S.), Fondation pour la Recherche Médicale (C.T., M.O. and M.D.), Type 1 Diabetes TrialNet (M.B.), Agence Nationale de la Recherche (NR-11-IDEX-0005-02 Laboratory of Excellence INFLAMEX to A.L.), Fondation pour la Recherche Médicale (DEQ20140329520 to A.L.), the INSERM cross-cutting program on microbiota (A.L.), the European Foundation for the Study of Diabetes–Juvenile Diabetes Research Foundation–Lilly (A.L.), the Département Hospitalo-Universitaire on Autoimmune and Hormonal Diseases (A.L.), the Ministry of Research (O.R.) and Aide aux Jeunes Diabétiques (I.N.).

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O.R., J.D.s. and L.B. performed most of the experiments and data analysis; I.N., C.T., L.C. and B.K. performed experiments and data analysis; M.O. and M.D. participated in experiments with the EndoC-β1 cell line; M.S. and O.L. provided Mr1−/− C57BL/6 and Mr1−/− B6-MAITCAST mice and reagents; A.C., J.R. and J.M. provided mouse MR1 tetramers; J.R., J.M., R.S. and O.L. provided intellectual input; M.B., M.P. and J.B. characterized patients and provided human samples; O.R., I.N. and A.L. wrote the manuscript; and A.L. supervised the work.

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Correspondence to Agnès Lehuen.

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Rouxel, O., Da silva, J., Beaudoin, L. et al. Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes. Nat Immunol 18, 1321–1331 (2017). https://doi.org/10.1038/ni.3854

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