2. Academic Validation
  3. Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

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

  • J Exp Med. 2021 Aug 2;218(8):e20202512. doi: 10.1084/jem.20202512.
J Justin Milner 1,  Clara Toma 1,  Sara Quon 1,  Kyla Omilusik 1,  Nicole E Scharping 1,  Anup Dey 2,  Miguel Reina-Campos 1,  Hongtuyet Nguyen 1,  Adam J Getzler 3,  Huitian Diao 3,  Bingfei Yu 1,  Arnaud Delpoux 1,  Tomomi M Yoshida 1,  Deyao Li 4 5,  Jun Qi 4 5,  Adam Vincek 6,  Stephen M Hedrick 1 7,  Takeshi Egawa 8,  Ming-Ming Zhou 6,  Shane Crotty 9 10,  Keiko Ozato 2,  Matthew E Pipkin 3,  Ananda W Goldrath 1
Affiliations

Affiliations

  • 1 Division of Biological Sciences, University of California San Diego, La Jolla, CA.
  • 2 Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
  • 3 Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • 5 Department of Medicine, Harvard Medical School, Boston, MA.
  • 6 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 7 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA.
  • 8 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
  • 9 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
  • 10 Division of Infectious Diseases, Department of Medicine, University of California San Diego, La Jolla, CA.
PMID: 34037670 DOI: 10.1084/jem.20202512
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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