biostudies-literatureTay REMassachusetts Institute of TechnologyDr. Miriam and Sheldon G. Adelson Medical Research FoundationDana-Farber/Harvard Cancer CenterNCI NIH HHSA*STARNational Institutes of HealthNIAMS NIH HHSe20191453https://www.ebi.ac.uk/biostudies/studies/S-EPMC7336313biostudies-literatureUnknown217(7)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 The Journal of experimental medicineHdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells.PMC7336313P01 CA163222NCI R01 CA238039R01 AR043369R01 AR043369-19R01 CA222871R01 CA238039R01 AR072304Tay REWucherpfennig KWLong HWCejas PXie YWeng QYBrown MOlawoyin OFisher DEIto YKim HJMeyer CAfalseHdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells.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 2020-01-01T00:00:00Z2020 Jul2026-04-18T03:07:44.76Z2026-04-18T03:06:29.515ZS-EPMC73363133237440210.1084/jem.20191453