Stress-induced beta cell dedifferentiation prior to immune cell infiltration prevents type 1 diabetes [Single]

Immune-mediated destruction of insulin-producing ß-cells causes type 1 diabetes (T1D). However, how ß-cells themselves participate in the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in ß-cells of non-obese diabetic (NOD) mice in early stages of disease results in preserved ß-cell function, substantially reduced islet immune cell infiltration, and ß-cell apoptosis leading to protection from T1D. NOD mice that lack the UPR sensor IRE1a in ß-cells show greatly reduced expression of ß-cell identity markers, islet autoantigens, and genes involved in antigen presentation. These mice exhibit upregulation of immune inhibitory markers in ß-cells and significantly less cytotoxic CD8+ T cells in the pancreas. Our results indicate that triggering transient ß-cell dedifferentiation via targeting a specific branch of the UPR in ß-cells, prior to insulitis, allow ß-cells to escape from immune destruction and may be used as a novel preventive strategy for high-risk individuals. Overall design: Single cell sequencing of 5-week-old IRE1afl/fl (WT; n=1) and IRE1aß-/- (KO; n=2) mice were done.