SUN-562 UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors

Abstract Disclosure: H. Chen: None. H. Wang: None. L. Kohn: None. D. Sailer: None. S. Zhang: None. E. McCarthy: None. M. Seyedsadr: None. Z. Zhou: None. X. Yin: None. N. Wilkinson: None. J.G. Ortega: None. M. Lechner: None. W. Hugo: None. M.A. Su: None. Type 1 Diabetes Mellitus (T1D) is an autoimmune disease caused by unremitting immune attack on pancreas insulin-producing beta cells. Persistence of the autoimmune response is mediated by TCF1+ Ly108+ progenitor CD8+ T (Tprog) cells, a stem-like population that gives rise to exhausted effectors with limited cytolytic function in chronic virus infection and cancer. What paradoxically drives Tprog conversion to highly cytolytic effectors in T1D, however, remains unclear. Here, we show that the epigenetic regulator UTX controls diabetogenic CD8+ Tprog differentiation by poising chromatin for transition to a cytolytic effector state. Indeed, deletion of UTX function in T cells impairs conversion of Tprog to autoimmune effectors and protects mice from spontaneous diabetes, as well as an aggressive form of autoimmune diabetes induced by anti-PD1 cancer immunotherapy. Furthermore, short-term treatment with UTX inhibitor GSKJ4 similarly protects from T1D, highlighting the therapeutic potential of targeting UTX-mediated mechanisms to break unremitting autoimmune responses. Presentation: Sunday, July 13, 2025