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

International audience; Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of pancreatic islet β-cells that produce insulin, in the context of an underlying multigenetic inheritance 1. When most of the β-cells are destroyed or non-functional, the ensuing lack of insulin results in hyperglycemia and requires lifelong insulin-replacement therapy 1. The physiopathology of T1D involves inappropriate activation of both the innate immune system and adaptive immune system, which induces loss of self-tolerance and islet destruction 2-5. T1D is characterized by the presence of anti-islet autoantibodies and auto-reactive T cells. Innate immune cells are involved at various stages of the disease and are particularly important for the initiation of the local immune response in the pancreas and the pancreatic lymph nodes (PLNs) 2,4. Published data have highlighted the role of the intestinal microbiota in T1D by transfer experiments in mice of the non-obese diabetic (NOD) strain 6-8 and gut microbiota differences in children that are associated with the development of T1D 9-11. Several studies have also described alterations to the gut mucosa in NOD mice and patients with T1D 12-16. Mucosal-associated invariant T cells (MAIT cells) are innate-like T cells that recognize bacterial metabolites derived from the synthesis of riboflavin and presented by the monomorphic major histocompatibility complex (MHC) class-I-related protein MR1 (refs. 17-19). These non-conventional T cells express a conserved αβ T cell antigen receptor (TCR) that consists of an invariant TCR α-chain (α-chain variable region 7.2 and α-chain joining regions 33, 20 and12 (V α 7.2-J α 33,20,12) in humans and V α 19-J α 33 in mice) with a restricted set of TCR β-chains. MAIT cells produce various cytokines, such as TNF, IFN-γ, IL-17 and granzyme B (GzB), that participate in tissue inflammation and cell death 17,20-28. The nearly complete absence of MAIT cells in germ-free mice 17,29 and their physiological localization at mucosal sites, including the gut 17,21 , suggest a strong interaction with the microbiota. Here we found alterations in MAIT cells in patients with T1D and, through the use of NOD mice, revealed a protective role for MAIT cells directed against T1D. The localization and function of MAIT cells highlight their key role in the maintenance of gut integrity whereby they control the development of autoimmune responses to pancreatic β-cells. RESULTS Alterations in MAIT cells in children with recent-onset T1D We first began our investigation of MAIT cells in T1D by analyzing the frequency and phenotype of MAIT cells in fresh peripheral Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic b-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.