Immune-mediated destruction of insulin-producing β cells causes type 1 diabetes (T1D). However, how β cells participate in their own destruction during 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 by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of β cells, resulting in substantially reduced islet immune cell infiltration and β cell apoptosis. Single-cell and whole-islet transcriptomics analyses of immature β cells revealed remarkably diminished expression of β cell autoantigens and MHC class I components, and upregulation of immune inhibitory markers. IRE1α-deficient mice exhibited significantly fewer cytotoxic CD8+ T cells in their pancreata, and adoptive transfer of their total T cells did not induce diabetes in Rag1-/- mice. Our results indicate that inducing β cell dedifferentiation, prior to insulitis, allows these cells to escape immune-mediated destruction and may be used as a novel preventive strategy for T1D in high-risk individuals.

中文翻译：

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IRE1α 缺失诱导的 β 细胞去分化可预防 1 型糖尿病。

免疫介导的产生胰岛素的 β 细胞的破坏导致 1 型糖尿病 (T1D)。然而，人们对β细胞在疾病过程中如何参与自身的破坏知之甚少。在这里，我们报告通过在胰岛炎之前删除UPR传感器IRE1α来调节非肥胖糖尿病（NOD）小鼠β细胞中的未折叠蛋白反应（UPR）诱导β细胞的瞬时去分化，导致胰岛免疫细胞浸润显着减少和β细胞凋亡。未成熟 β 细胞的单细胞和全胰岛转录组学分析显示 β 细胞自身抗原和 MHC I 类成分的表达显着降低，免疫抑制标志物上调。IRE1α 缺陷小鼠胰腺中的细胞毒性 CD8+ T 细胞显着减少，并且他们的总 T 细胞的过继转移不会在 Rag1-/- 小鼠中诱发糖尿病。我们的研究结果表明，在胰岛炎之前诱导 β 细胞去分化可使这些细胞逃避免疫介导的破坏，并可用作高危人群中 T1D 的新预防策略。