Early senescence-induced immunosuppressive ß-cell secretome prevents type 1 diabetes

During the progression of type 1 diabetes (T1D), ß-cells are exposed to significant stress and therefore require adaptive responses to survive. The adaptive mechanisms that can preserve ß-cell function and survival in the face of autoimmunity remain unclear. Here we show that deletion of the unfolded protein response genes, Atf6a or Ire1a, in ß-cells of NOD mice prior to insulitis generates a p21-driven early senescence phenotype and altered ß-cell secretome that significantly enhances leukemia inhibitory factor-mediated recruitment of M2 macrophages to the islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause resolution of islet inflammation, removal of terminally senesced ß-cells, reduction of ß-cell apoptosis, and prevention of T1D. We further demonstrate that p21-mediated early senescence signature is conserved in residual ß-cells of T1D patients. Our findings reveal a previously unrecognized link between ß-cell UPR and senescence that, if leveraged, may represent a novel therapeutic strategy for T1D. Overall design: mRNA sequencing of 6-week-old Atf6fl/fl (WT) and Atf6ß-/- (KO) mice were done with n=3-4 per group