Stress-induced (3 cell early senescence confers protection against type 1 diabetes

During the progression of type 1 diabetes (T1D), (3 cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve (3 cell function and sur-vival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6a or Ire1a in (3 cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the (3 cell secretome that significantly enhances the leu-kemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflamma-tion, the removal of terminally senesced (3 cells, the reduction of (3 cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual (3 cells of T1D patients. Our findings reveal a previously unrecognized link between (3 cell UPR and senes-cence that, if leveraged, may represent a novel preventive strategy for T1D.