In vivo CD8 T cell CRISPR screening reveals control by Fli1 in infection and cancer.

Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (T)-driving transcription factors (TFs), the transcriptional coordination of T biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining T biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced T responses without compromising memory or exhaustion precursors. Fli1 restrained T lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven T biology. CD8 T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8 T cell transcriptional landscape from excessive ETS:RUNX-driven T cell differentiation. Moreover, genetic deletion of Fli1 improves T differentiation and protective immunity in infections and cancer.