Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes
Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes
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DOI：
10.1016/j.cmet.2020.03.002
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发表时间：
2020-04-07
期刊：
影响因子：
29
通讯作者：
Engin, Feyza
中科院分区：
文献类型：
--
作者：
Lee, Hugo;Lee, Yong-Syu;Engin, Feyza
免疫介导的胰岛素产生β细胞的破坏导致1型糖尿病（T1 D）。然而，β细胞在疾病过程中如何参与自身的破坏却知之甚少。在这里，我们报告，通过在胰岛炎之前删除UPR传感器IRE 1 α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和β细胞凋亡大幅减少。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类成分的表达显著减少，免疫抑制标志物上调。IRE 1 α缺陷小鼠胰腺中的细胞毒性CD 8 T细胞显著减少，过继转移其总T细胞不会诱导Rag 1（-/-）小鼠发生糖尿病。我们的研究结果表明，诱导β细胞去分化，胰岛炎之前，允许这些细胞逃避免疫介导的破坏，并可能被用作一种新的预防策略T1 D在高风险的个人。
Immune-mediated destruction of insulin-producing beta cells causes type 1 diabetes (T1D). However, how beta cells participate in their own destruction during the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in beta cells of non-obese diabetic (NOD) mice by deleting the UPR sensor IRE1 alpha prior to insulitis induced a transient dedifferentiation of beta cells, resulting in substantially reduced islet immune cell infiltration and beta cell apoptosis. Single-cell and whole-islet transcriptomics analyses of immature beta cells revealed remarkably diminished expression of beta cell autoantigens and MHC class I components, and upregulation of immune inhibitory markers. IRE1 alpha-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 beta cell dedifferentiation, prior to insulitis, allows these cells to escape immune-mediated destruction and may be used as a novel preventive strategy for T1 D in high-risk individuals.