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.
Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection
A. Delpoux died on June 30, 2019.
A.W. Goldrath reported “other” from Pandion Therapeutics and “other” from ArsenalBio outside the submitted work, and is on the SAB of Pandion Therapeutics and ArsenalBio. J. Qi reported “other” from Epiphanes outside the submitted work. No other disclosures were reported.
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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; Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection. J Exp Med 2 August 2021; 218 (8): e20202512. doi: https://doi.org/10.1084/jem.20202512
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