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

被引：132

作者：

Chen, Zeyu ^{[1
,2
,3
,6
]}

Arai, Eri ^{[3
,4
]}

Khan, Omar ^{[1
,2
,9
]}

Zhang, Zhen ^{[4
,5
]}

Ngiow, Shin Foong ^{[1
,2
,6
]}

He, Yuan ^{[7
]}

Huang, Hua ^{[1
,2
,4
,5
]}

Manne, Sasikanth ^{[1
,2
]}

Cao, Zhendong ^{[3
,4
]}

Baxter, Amy E. ^{[1
,2
]}

Cai, Zhangying ^{[1
,2
]}

Freilich, Elizabeth ^{[3
]}

Ali, Mohammed A. ^{[1
,2
]}

Giles, Josephine R. ^{[1
,2
]}

Wu, Jennifer E. ^{[1
,2
]}

Greenplate, Allison R. ^{[1
,2
]}

Hakeem, Mohamed A. ^{[1
,2
]}

Chen, Qingzhou ^{[3
,4
]}

Kurachi, Makoto ^{[1
,2
,10
]}

Nzingha, Kito ^{[1
,2
]}

Ekshyyan, Viktoriya ^{[1
,2
]}

Mathew, Divij ^{[1
,2
]}

Wen, Zhuoyu ^{[3
]}

Speck, Nancy A. ^{[5
]}

Battle, Alexis ^{[7
,8
]}

Berger, Shelley L. ^{[4
,5
]}

Wherry, E. John ^{[1
,2
,6
]}

Shi, Junwei ^{[2
,3
,4
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Canc Biol, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Epigenet Inst, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA

[6] Univ Penn, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

[7] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA

[8] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA

[9] Arsenal Biosci, San Francisco, CA USA

[10] Kanazawa Univ, Dept Biochem 1, Grad Sch Med Sci, Kanazawa, Ishikawa, Japan

来源：

CELL | 2021年 / 184卷 / 05期

关键词：

TRANSCRIPTION FACTOR IRF4; READ ALIGNMENT; EXHAUSTION; EFFECTOR; PD-1; CHROMATIN; GENE; EXPRESSION; CHECKPOINT; REGULATOR;

D O I：

10.1016/j.cell.2021.02.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (TFs), the transcriptional coordination of T-EFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key 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.

引用

页码：1262 / +

页数：41

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