Type 1 diabetes is an autoimmune disease resulting from the destruction of pancreatic-beta cells by the immune system involving innate and adaptive immune cells. Mucosal-associated invariant T (MAIT) cells are innate-like T-cells recognizing bacterial riboflavin-precursor derivatives presented by the MHC-I related molecule, MR1. Since T1D is associated with gut microbiota modification, we investigated MAIT cells in this pathology. In T1D patients and non-obese diabetic mice, we detected MAIT cell alterations, including increased granzyme B production, which occur before disease onset. Analysis of NOD mice deficient for MR1 and therefore lacking MAIT cells revealed a loss of gut integrity, increased anti-islet responses associated with exacerbated diabetes. Altogether our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. MAIT cell monitoring could represent a new biomarker in T1D while their manipulation may open new therapeutic strategies.

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human β cell dedifferentiation. Using the functional human β cell line EndoC-βH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in β cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human β cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human β cell dedifferentiation.