HDAC3 IS AN EPIGENETIC INHIBITOR OF THE CYTOTOXICITY PROGRAM IN CD8 T CELLS [RNA-seq]

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. Overall design: CD8 T cells were magnetically isolated from OT-I transgenic mice and activated by co-culture with irradiated, OVA peptide-pulsed bone marrow-derived dendritic cells. We performed three replicates per experimental condition. For drug/no drug treatment experiments, the same source material was used for both experiments. For KO vs WT experiments, we used cells collected from KO and WT littermates as the source material, respectively.