| First Author | Lee H | Year | 2020 |
| Journal | Cell Metab | Volume | 31 |
| Issue | 4 | Pages | 822-836.e5 |
| PubMed ID | 32220307 | Mgi Jnum | J:287744 |
| Mgi Id | MGI:6406641 | Doi | 10.1016/j.cmet.2020.03.002 |
| Citation | Lee H, et al. (2020) Beta Cell Dedifferentiation Induced by IRE1alpha Deletion Prevents Type 1 Diabetes. Cell Metab 31(4):822-836.e5 |
| abstractText | 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 IRE1alpha 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. IRE1alpha-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 T1D in high-risk individuals. |
