1. Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells.
- Author
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Tay RE, Olawoyin O, Cejas P, Xie Y, Meyer CA, Ito Y, Weng QY, Fisher DE, Long HW, Brown M, Kim HJ, and Wucherpfennig KW
- Subjects
- Acetylation drug effects, Acrylamides pharmacology, Animals, Antigens metabolism, Base Sequence, CD8-Positive T-Lymphocytes drug effects, Core Binding Factor Alpha 3 Subunit metabolism, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases deficiency, Histones metabolism, Lymph Nodes drug effects, Lymph Nodes metabolism, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Lymphocytic choriomeningitis virus physiology, Lysine metabolism, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Phenylenediamines pharmacology, Positive Regulatory Domain I-Binding Factor 1 metabolism, Transcription, Genetic drug effects, CD8-Positive T-Lymphocytes immunology, Epigenesis, Genetic drug effects, Histone Deacetylases metabolism, T-Lymphocytes, Cytotoxic drug effects
- Abstract
Cytotoxic T cells play a key role in adaptive immunity by killing infected or cancerous cells. While the transcriptional control of CD8 T cell differentiation and effector function following T cell activation has been extensively studied, little is known about epigenetic regulation of these processes. Here we show that the histone deacetylase HDAC3 inhibits CD8 T cell cytotoxicity early during activation and is required for persistence of activated CD8 T cells following resolution of an acute infection. Mechanistically, HDAC3 inhibits gene programs associated with cytotoxicity and effector differentiation of CD8 T cells including genes encoding essential cytotoxicity proteins and key transcription factors. These data identify HDAC3 as an epigenetic regulator of the CD8 T cell cytotoxicity program., Competing Interests: Disclosures: Dr. Fisher reported a financial interest in Soltego, Inc., a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. Dr. Fisher's interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. Dr. Brown reported grants from Novartis and personal fees from H3 Biomedicine, Kronos Bio, Aleta Biotherapeutics, and GV20 Therapeutics outside the submitted work. Dr. Wucherpfennig reported grants from Novartis during the conduct of the study; personal fees from TCR2 Therapeutics, T-Scan Therapeutics, Immunitas Therapeutics, and Nextechinvest outside the submitted work. No other disclosures were reported., (© 2020 Tay et al.)
- Published
- 2020
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