Interferons and STAT1 dynamically modulate integrated stress response outcomes in CD8 T cells

Type I interferons (IFN-I) drive both protective and pathological CD8 T cell responses. Patients with activating STAT1 mutations exhibit enhanced IFN responses with T cell dysfunction and autoimmunity; however, mechanisms underlying excess versus impaired response remain unclear. We used mouse models expressing a STAT1 mutation ( Stat1 -T385M) ubiquitously or T-cell selectively to dissect T cell-intrinsic versus cell-extrinsic actions of activating STAT1. Global Stat1 -T385M expression had increased lethality upon acute viral infection with CD8 T cell dysfunction marked by stress response activation rather than classical exhaustion. This dysfunction was extrinsic, as T-cell-restricted Stat1 -T385M preserved expansion, cytokine production, and checkpoint receptor expression. However, intrinsic Stat1 -T385M reshaped differentiation by suppressing T-bet and effector programs while upregulating a stress signature seen in memory lymphocytes. The extrinsic-intrinsic switch depended on IFN-I magnitude, with exaggerated levels triggering a pro-apoptotic stress response. Therefore, STAT1 works as a rheostat balancing CD8 differentiation and stress, as a basis for interferonopathies.