Tet2 modulates ER stress responses related to β-cell death and autoimmunity in diabetes

We found that beta cells from TET2-deficient mice were protected from killing in a model of autoimmune Type 1 diabetes, but the mechanism of protection and specific cell types affected by TET2 loss were unknown. Herein we show that in Tet2-deficient NOD mice transplanted with wild-type bone marrow, there are fewer islet infiltrating lymphocytes beginning 8-10 weeks after transplant, which was seen primarily among CD4⁺ T-cells. Transcription factor binding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To determine whether there were similar effects in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that TET2 (TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.