TY - JOUR
T1 - Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection
AU - Milner, J. Justin
AU - Toma, Clara
AU - Quon, Sara
AU - Omilusik, Kyla
AU - Scharping, Nicole E.
AU - Dey, Anup
AU - Reina-Campos, Miguel
AU - Nguyen, Hongtuyet
AU - Getzler, Adam J.
AU - Diao, Huitian
AU - Yu, Bingfei
AU - Delpoux, Arnaud
AU - Yoshida, Tomomi M.
AU - Li, Deyao
AU - Qi, Jun
AU - Vincek, Adam
AU - Hedrick, Stephen M.
AU - Egawa, Takeshi
AU - Zhou, Ming Ming
AU - Crotty, Shane
AU - Ozato, Keiko
AU - Pipkin, Matthew E.
AU - Goldrath, Ananda W.
N1 - Funding Information:
This work was funded by National Institutes of Health grants AI132122 (A.W. Goldrath), U19AI109976 (A.W. Goldrath, M.E. Pipkin, and S. Crotty), K99/R00 CA234430-01 (J.J. Milner), and R01AI130152 (T. Egawa), the Leukemia and Lymphoma Society Scholar Award (T. Egawa) and a Cancer Research Institute Postdoctoral Fellowship (M. Reina-Campos).
Publisher Copyright:
© 2021 Milner et al.
PY - 2021/5/26
Y1 - 2021/5/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85107043181&partnerID=8YFLogxK
U2 - 10.1084/jem.20202512
DO - 10.1084/jem.20202512
M3 - Article
C2 - 34037670
AN - SCOPUS:85107043181
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 8
M1 - e20202512
ER -