Bromodomain Protein BRD4 Directs and Sustains CD8 T Cell Differentiation During Infection

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2021 May 26

PMID 34037670

Citations 15

Authors

J Justin Milner

Clara Toma

Sara Quon

Kyla Omilusik

Nicole E Scharping

Anup Dey

Miguel Reina-Campos

Hongtuyet Nguyen

Adam J Getzler

Huitian Diao

Bingfei Yu

Arnaud Delpoux

Tomomi M Yoshida

Deyao Li

Jun Qi

Adam Vincek

Stephen M Hedrick

Takeshi Egawa

Ming-Ming Zhou

Shane Crotty

Keiko Ozato

Matthew E Pipkin

Ananda W Goldrath

Affiliations

Soon will be listed here.

Abstract

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 super-enhancers 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.

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