Loss of gut barrier integrity triggers autoimmune diabetes through microbiota-induced activation of islet-reactive T cells

Abstract

Abstract Recent evidence suggests that the intestinal environment and, specifically, modifications of the microbiome profile, regulate the pathogenesis of extra-intestinal autoimmune diseases such as Type 1 Diabetes (T1D) by inducing intestinal inflammation and increasing gut permeability. Although low-grade intestinal inflammation and alterations of gut barrier integrity are found in humans and animal models of T1D, a direct causal link between enteropathy and triggering of beta cell autoimmunity is yet to be established. Here we show that breakage of the gut barrier integrity (by low-dose DSS administration) in BDC2.5XNOD mice carrying a transgenic TCR specific for a beta cell-autoantigen leads to activation of the islet-reactive T cell clone (BDC2.5) within the gut mucosa and onset of T1D. The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota. Importantly, we found that gut microbial antigens are directly capable to activate the diabetogenic BDC2.5 T cells with a TCR-mediated mechanism. Our results indicate that loss of the intestinal barrier continuity is directly responsible for activation of islet-specific T cells by commensal gut microbiota and provide a strong rationale to design innovative therapeutic interventions in “at risk” individuals aimed at restoring gut barrier integrity to prevent T1D.