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

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 (T) cells, a stem-like population that gives rise to exhausted effectors with limited cytolytic function in chronic virus infection and cancer. What paradoxically drives T conversion to highly cytolytic effectors in T1D, however, remains unclear. Here, we show that the epigenetic regulator UTX controls diabetogenic CD8+ T differentiation by poising chromatin for transition to a cytolytic effector state. Indeed, deletion of UTX function in T cells impairs conversion of T 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.