Gfi1 controls the formation of effector CD8+ T cells during chronic infection and cancer [RNA]
During chronic infection and tumor progression, CD8+ T cells gradually lose their cytotoxic effector function and become “exhausted”. These “exhausted” CD8+ T cells are highly heterogenous and comprised of various subsets, including a self-renewing progenitor subset that gives rise to Ly108-CX3CR1+ effector cells with some cytotoxic capabilities. Generation of these effectors is essential for the control (although limited) of chronic infection and tumor. However, the precise cues and mechanisms directing their formation and maintenance remains incompletely understood. In this study, using genetic mouse models challenged with the LCMV clone 13 infection and syngeneic MB49 urothelial adenocarcinoma, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in “exhausted” CD8+ T cells. By controlling chromatin accessibility and transcriptomic programs, Gfi1 governs the generation of the effector cells. Deletion of Gfi1 in T cells arrests the progenies from progenitors in a Ly108+CX3CR1+ Transitional state, without further differentiation into effector cells. Given the programmable chromatin profile of these transitional cells, we reason that they are a better target than the highly irreprogrammable terminally differentiated cells for therapeutic interventions to combat chronic infection and cancer. Our results show that Gfi1 is a novel epigenetic and transcriptional regulator of CD8+ T cell exhaustion. Overall design: Gfi1fl/fl CD4cre-/- (Wildtype) or Gfi1fl/fl CD4cre-/- (Gfi1cKO) mice were infected with LCMV clone 13. GP33+ antigen specific CD8+ T cell subsets from wildtype (Progenitor, Effector, Transitional, and Terminally Exhausted) and Gfi1cKO (Progenitor and Transitional) mice were FACS sorted 30 days post infection. Bulk RNA sequencing was used to investigate gene expression in sorted cells. Samples are pooled biological replicates. Naive CD8+ T cells isolated from uninfected wildtype and Gfi1cKO mice were included as controls.