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Bromodomain and extraterminal domain (BET) proteins help direct the differentiation of helper T cell subsets, but their role in activated T cell function has not been described in detail. In this study, we investigate various consequences of epigenetic perturbation in human T lymphocytes using MK-8628, a potent and highly selective inhibitor of BET proteins. MK-8628 reduces the expression of canonical transcripts directing the proliferation, activation, and effector function of T lymphocytes. Treatment with MK-8628 abolishes the expression of key cyclins required for cell cycle progression and induces G1 cell cycle arrest in TCR-activated lymphocytes. This antiproliferative phenotype partially results from T lymphocyte apoptosis, which is exacerbated by MK-8628. In naive and memory T cell subsets, MK-8628 antagonizes T cell activation and suppresses polyfunctional cytokine production. Collectively, our results describe potent immunosuppressive effects of BET inhibition on human T cell biology. These results have important implications for immune modulatory targeting of BET proteins in the settings of T cell-driven autoimmune inflammation.
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
October 2013,
The Journal of experimental medicine,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
January 2020,
Endocrine,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
January 2021,
Cancer immunology, immunotherapy : CII,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
September 2016,
The Journal of clinical investigation,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
June 2015,
Molecular cell,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
December 2012,
Biochemical and biophysical research communications,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
August 2022,
Cell death & disease,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
May 2017,
Science translational medicine,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
February 2014,
Clinical cancer research : an official journal of the American Association for Cancer Research,
Peter Georgiev, and
Yun Wang, and
Eric S Muise, and
Madhavi L Bandi, and
Wendy Blumenschein, and
Manjiri Sathe, and
Elaine M Pinheiro, and
Stuart D Shumway
March 2018,
Cancer prevention research (Philadelphia, Pa.),
