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Regulatory T cells (Tregs) protect against autoimmunity. In type 1 diabetes (T1D), Tregs slow the progression of beta cell autoimmunity within pancreatic islets. Increasing the potency or frequency of Tregs can prevent diabetes, as evidenced by studies in the nonobese diabetic (NOD) mouse model for T1D. We report herein that a significant proportion of islets Tregs in NOD mice expressGata3. The expression ofGata3was correlated with the presence of IL-33, a cytokine known to induce and expand Gata3+Tregs. Despite significantly increasing the frequency of Tregs in the pancreas, exogenous IL-33 was not protective. Based on these data, we hypothesized that Gata3 is deleterious to Treg function in autoimmune diabetes. To test this notion, we generated NOD mice with a Treg-specific deletion ofGata3. We found that deletingGata3in Tregs strongly protected against diabetes. Disease protection was associated with a shift of islet Tregs toward a suppressive CXCR3+Foxp3+population. Our results suggest that islet Gata3+Tregs are maladaptive and that this Treg subpopulation compromises the regulation of islet autoimmunity, contributing to diabetes onset.

Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, we show that deleting RNLS, a genome-wide association study candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modelling identified the U.S. Food and Drug Administration-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, thus leading to disease reversal. Furthermore, pargyline prevented or delayed diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.

Genome-wide association studies have implicated more than 50 genomic regions in type 1 diabetes (T1D). A T1D region at chromosome 16p13.13 includes the candidate genes CLEC16A and DEXI. Conclusive evidence as to which gene is causal for the disease association of this region is missing. We previously reported that Clec16a deficiency modified immune reactivity and protected against autoimmunity in the nonobese diabetic (NOD) mouse model for T1D. However, the diabetes-associated SNPs at 16p13.13 were described to also impact on DEXI expression and others have argued that DEXI is the causal gene in this disease locus. To help resolve whether DEXI affects disease, we generated Dexi knockout (KO) NOD mice. We found that Dexi deficiency had no effect on the frequency of diabetes. To test for possible interactions between Dexi and Clec16a, we intercrossed Dexi KO and Clec16a knockdown (KD) NOD mice. Dexi KO did not modify the disease protection afforded by Clec16a KD. We conclude that Dexi plays no role in autoimmune diabetes in the NOD model. Our data provide strongly suggestive evidence that CLEC16A, not DEXI, is causal for the T1D association of variants in the 16p13.13 region.

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.

In the version of this Article originally published, the asterisks indicating statistical significance were missing from Supplementary Figure 6; the file with the correct figure is now available.