Summary

Improving effector activity of antigen specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (T EFF )-driving transcription factors (TF), the transcriptional coordination of T EFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a novel mechanism restraining T EFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced T EFF responses without compromising memory or exhaustion precursors. Fli1 restrained T EFF 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 EFF 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 EFF cell differentiation. Moreover, genetic deletion of Fli1 improves T EFF differentiation and protective immunity in infections and cancer.