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In vivo CRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer

By Zeyu Chen, Eri Arai, Omar Khan, Zhen Zhang, Shin Foong Ngiow, Yuan He, Hua Huang, Sasikanth Manne, Zhendong Cao, Amy E. Baxter, Zhangying Cai, Elizabeth Freilich, Mohammed A. Ali, Josephine R. Giles, Jennifer E Wu, Allison R. Greenplate, Makoto Kurachi, Kito Nzingha, Viktoriya Ekshyyan, Zhuoyu Wen, Nancy A Speck, Alexis Battle, Shelley L Berger, E John Wherry, Junwei Shi

Posted 20 May 2020
bioRxiv DOI: 10.1101/2020.05.20.087379

Improving effector activity of antigen specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TF), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a novel mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF 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 TEFF 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 TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer ### Competing Interest Statement The authors have declared no competing interest.

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