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. 2020 Apr 7;31(4):822-836.e5.
doi: 10.1016/j.cmet.2020.03.002. Epub 2020 Mar 26.

Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes

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Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes

Hugo Lee et al. Cell Metab. .

Abstract

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.

Keywords: ER stress; IRE1; NOD; RNA-seq; UPR; beta cell; dedifferentiation; islet; single cell; type 1 diabetes.

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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