Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

被引：25

作者：

Milner, J. Justin ^{[1
]}

Toma, Clara ^{[1
]}

Quon, Sara ^{[1
]}

Omilusik, Kyla ^{[1
]}

Scharping, Nicole E. ^{[1
]}

Dey, Anup ^{[2
]}

Reina-Campos, Miguel ^{[1
]}

Nguyen, Hongtuyet ^{[1
]}

Getzler, Adam J. ^{[3
]}

Diao, Huitian ^{[3
]}

Yu, Bingfei ^{[1
]}

Delpoux, Arnaud ^{[1
]}

Yoshida, Tomomi M. ^{[1
]}

Li, Deyao ^{[4
,5
]}

Qi, Jun ^{[4
,5
]}

Vincek, Adam ^{[6
]}

Hedrick, Stephen M. ^{[1
,7
]}

Egawa, Takeshi ^{[8
]}

Zhou, Ming-Ming ^{[6
]}

Crotty, Shane ^{[9
,10
]}

Ozato, Keiko ^{[2
]}

Pipkin, Matthew E. ^{[3
]}

Goldrath, Ananda W. ^{[1
]}

机构：

[1] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA

[2] NICHHD, Div Dev Biol, NIH, Bethesda, MD 20892 USA

[3] Scripps Res Inst, Dept Immunol & Microbiol, Jupiter, FL USA

[4] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[6] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA

[7] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[8] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[9] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA

[10] Univ Calif San Diego, Dept Med, Div Infect Dis, La Jolla, CA 92093 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2021年 / 218卷 / 08期

基金：

美国国家卫生研究院;

关键词：

TERMINAL DIFFERENTIATION; TRANSCRIPTION FACTORS; SELECTIVE-INHIBITION; P-TEFB; C-MYC; MEMORY; EFFECTOR; EXPRESSION; ID2; MAINTENANCE;

D O I：

10.1084/jem.20202512

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific superenhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.

引用

页数：17

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