Gfi1 controls the formation of effector-like CD8(+) T cells during chronic infection and cancer.

During chronic infection and tumor progression, CD8(+) T cells lose their effector functions and become exhausted. These exhausted CD8(+) T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8(+) T cells. During chronic LCMV Clone 13 infection, a previously under-described Ly108(+)CX(3)CR1(+) subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108(+)CX(3)CR1(+) cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8(+) T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8(+) T cells.