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

Immune-mediated destruction of insulin-producing β-cells causes type 1 diabetes (T1D). However, how β-cells themselves participate in the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in β-cells of non-obese diabetic (NOD) mice in early stages of disease results in preserved β-cell function, substantially reduced islet immune cell infiltration, and β-cell apoptosis leading to protection from T1D. NOD mice that lack the UPR sensor IRE1α in β-cells show greatly reduced expression of β-cell identity markers, islet autoantigens, and genes involved in antigen presentation. These mice exhibit upregulation of immune inhibitory markers in β-cells and significantly less cytotoxic CD8+ T cells in the pancreas. Our results indicate that triggering transient β-cell dedifferentiation via targeting a specific branch of the UPR in β-cells, prior to insulitis, allow β-cells to escape from immune destruction and may be used as a novel preventive strategy for high-risk individuals. Single cell sequencing of 5-week-old IRE1αfl/fl (WT; n=1) and IRE1αβ-/- (KO; n=2) mice were done.