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

Nature Immunology volume 18, pages 1321–1331 (2017)Cite this article

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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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References

  1. Atkinson, M.A., Eisenbarth, G.S. & Michels, A.W. Type 1 diabetes. Lancet 383, 69–82 (2014).

    PubMed  Google Scholar 

  2. Diana, J. et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat. Med. 19, 65–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Anderson, M.S. & Bluestone, J.A. The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23, 447–485 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Lehuen, A., Diana, J., Zaccone, P. & Cooke, A. Immune cell crosstalk in type 1 diabetes. Nat. Rev. Immunol. 10, 501–513 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Bluestone, J.A., Herold, K. & Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293–1300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Markle, J.G.M. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

    CAS  PubMed  Google Scholar 

  8. Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Kostic, A.D. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17, 260–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Alkanani, A.K. et al. Alterations in intestinal microbiota correlate with susceptibility to type 1 diabetes. Diabetes 64, 3510–3520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 1551 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Alam, C. et al. Inflammatory tendencies and overproduction of IL-17 in the colon of young NOD mice are counteracted with diet change. Diabetes 59, 2237–2246 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alam, C. et al. Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice. Diabetologia 54, 1398–1406 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Bosi, E. et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824–2827 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Sapone, A. et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55, 1443–1449 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Badami, E. et al. Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes. Diabetes 60, 2120–2124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Corbett, A.J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Franciszkiewicz, K. et al. MHC class I-related molecule, MR1, and mucosal-associated invariant T cells. Immunol. Rev. 272, 120–138 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Magalhaes, I. et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125, 1752–1762 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Illés, Z., Shimamura, M., Newcombe, J., Oka, N. & Yamamura, T. Accumulation of Vα7.2-Jα33 invariant T cells in human autoimmune inflammatory lesions in the nervous system. Int. Immunol. 16, 223–230 (2004).

    Article  PubMed  Google Scholar 

  24. Serriari, N.-E. et al. Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin. Exp. Immunol. 176, 266–274 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen, Z. et al. Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. Mucosal Immunol. 10.1038/mi.2016.39 (2016).

  26. Le Bourhis, L. et al. MAIT cells detect and efficiently lyse bacterially-infected epithelial cells. PLoS Pathog. 9, e1003681 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jeffery, H.C. et al. Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1. J. Hepatol. 64, 1118–1127 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kurioka, A. et al. MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets. Mucosal Immunol. 8, 429–440 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Koay, H.-F. et al. A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage. Nat. Immunol. 17, 1300–1311 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Reantragoon, R. et al. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J. Exp. Med. 210, 2305–2320 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leete, P. et al. Differential insulitic profiles determine the extent of β-cell destruction and the age at onset of type 1 diabetes. Diabetes 65, 1362–1369 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Komulainen, J. et al. Clinical, autoimmune, and genetic characteristics of very young children with type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes Care 22, 1950–1955 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Ravassard, P. et al. A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J. Clin. Invest. 121, 3589–3597 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rahimpour, A. et al. Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers. J. Exp. Med. 212, 1095–1108 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cui, Y. et al. Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation. J. Clin. Invest. 125, 4171–4185 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Dudakov, J.A., Hanash, A.M. & van den Brink, M.R.M. Interleukin-22: immunobiology and pathology. Annu. Rev. Immunol. 33, 747–785 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rutz, S., Wang, X. & Ouyang, W. The IL-20 subfamily of cytokines--from host defence to tissue homeostasis. Nat. Rev. Immunol. 14, 783–795 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Costa, F.R.C. et al. Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset. J. Exp. Med. 213, 1223–1239 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Amrani, A. et al. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 406, 739–742 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Diana, J. et al. Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay. J. Exp. Med. 208, 729–745 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Turley, S., Poirot, L., Hattori, M., Benoist, C. & Mathis, D. Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198, 1527–1537 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fujimoto, K. et al. A new subset of CD103+CD8α+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity. J. Immunol. 186, 6287–6295 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Cerovic, V., Bain, C.C., Mowat, A.M. & Milling, S.W.F. Intestinal macrophages and dendritic cells: what's the difference? Trends Immunol. 35, 270–277 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Murphy, T.L. et al. Transcriptional control of dendritic cell development. Annu. Rev. Immunol. 34, 93–119 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Cho, Y.-N. et al. Mucosal-associated invariant T cell deficiency in systemic lupus erythematosus. J. Immunol. 193, 3891–3901 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Magalhaes, I., Kiaf, B. & Lehuen, A. iNKT and MAIT cell alterations in diabetes. Front. Immunol. 6, 341 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Toubal, A. & Lehuen, A. Lights on MAIT cells, a new immune player in liver diseases. J. Hepatol. 64, 1008–1010 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Maxwell, J.R. et al. Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. Immunity 43, 739–750 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Lee, J.S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mahon, J.L. et al. The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results. Pediatr. Diabetes 10, 97–104 (2009).

    Article  PubMed  Google Scholar 

  52. TrialNet - Information for Patients. Available at: https://www.diabetestrialnet.org/PathwayToPrevention/ (2017).

  53. Lochner, M. et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+Foxp3+ RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Huang, S. et al. MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proc. Natl. Acad. Sci. USA 106, 8290–8295 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Pickard, J.M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638–641 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Author notes

  1. Ophélie Rouxel, Jennifer Da silva and Lucie Beaudoin: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM U1016, Institut Cochin, Paris, France, and Université Paris Descartes, Paris, France

    Ophélie Rouxel, Jennifer Da silva, Lucie Beaudoin, Isabelle Nel, Céline Tard, Lucie Cagninacci, Badr Kiaf, Masaya Oshima, Marc Diedisheim, Raphael Scharfmann, Michel Polak, Jacques Beltrand & Agnès Lehuen

  2. CNRS, UMR8104, Paris, France

    Ophélie Rouxel, Jennifer Da silva, Lucie Beaudoin, Isabelle Nel, Céline Tard, Lucie Cagninacci, Badr Kiaf, Masaya Oshima, Marc Diedisheim, Raphael Scharfmann, Michel Polak, Jacques Beltrand & Agnès Lehuen

  3. Laboratoire d'Excellence INFLAMEX, Sorbonne Paris Cité,, Paris, France

    Ophélie Rouxel, Jennifer Da silva, Lucie Beaudoin, Isabelle Nel, Céline Tard, Lucie Cagninacci, Badr Kiaf & Agnès Lehuen

  4. INSERM U932, Institut Curie, Paris, France

    Marion Salou & Olivier Lantz

  5. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Alexandra Corbett & James McCluskey

  6. ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia

    Jamie Rossjohn

  7. Institute of Infection and Immunity, Cardiff University, Cardiff, UK

    Jamie Rossjohn

  8. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia

    Jamie Rossjohn

  9. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy, and TrialNet Clinical Center, San Raffaele Hospital, Milan, Italy

    Manuela Battaglia

  10. Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France

    Michel Polak & Jacques Beltrand

  11. Faculté de Médecine Paris Descartes, Université Sorbonne Paris Cité, Paris, France

    Michel Polak & Jacques Beltrand

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  1. Ophélie Rouxel
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Contributions

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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