HDAC3 IS AN EPIGENETIC INHIBITOR OF THE CYTOTOXICITY PROGRAM IN CD8 T CELLS [ChIP-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. 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. 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.

细胞毒性T细胞通过杀伤感染或癌变细胞，在适应性免疫中发挥关键作用。尽管T细胞活化后CD8阳性T细胞的分化与效应功能的转录调控已被广泛研究，但目前对这些过程的表观遗传调控机制仍知之甚少。本研究发现，组蛋白去乙酰化酶HDAC3（histone deacetylase HDAC3）可在T细胞活化早期抑制CD8阳性T细胞的细胞毒性功能，且对于急性感染清除后活化CD8阳性T细胞的持久性存续必不可少。从机制上讲，HDAC3可抑制与CD8阳性T细胞细胞毒性及效应分化相关的基因程序，包括编码核心细胞毒性蛋白与关键转录因子的基因。上述数据证实HDAC3是CD8阳性T细胞细胞毒性程序的表观遗传调控因子。本研究从OT-I转基因小鼠中磁分选分离CD8阳性T细胞，并将其与经辐照灭活、OVA肽脉冲致敏的骨髓源树突状细胞共培养以活化细胞。在给药与未给药处理实验中，两组均采用相同来源的实验材料；在基因敲除型（KO）与野生型（WT）对照实验中，分别采用来自KO小鼠及其同窝野生型小鼠的细胞作为实验材料。