NCoR1调控CD8 T细胞稳态和免疫应答的机制研究

Cytotoxic T cells, antigen-activated CD8 T cells, play a pivotal role in controlling virus infections and tumors. The activation of CD8 T cells involves in transcriptional activation and repression of many genes, which are regulated by epigenetic mechanisms. However, the transcriptional repression that controls the homeostasis of CD8 T cells and their differentiating to cytotoxic T cells remains not fully understood. Our published data demonstrated that nuclear receptor co-repressor 1 (NCoR1), a transcriptional repressor, is essentially required for a balanced T cell development in thymus. In addition, our preliminary studies revealed that NCoR1 was required for CD8 T cell homeostasis and optimal response to listeria infection. On the basis of the previous results, we plans to further study how NCoR1 controls CD8 T cell homeostasis and responses. Our study may reveal about the epigenetic mechanisms that NCoR1 regulates these two processes, having implications for both basic T cell biology and translational immunotherapy.

CD8 T细胞受抗原激活后成为杀伤性T细胞，在清除病毒感染和肿瘤细胞过程中起关键作用。该细胞激活过程涉及很多基因的转录激活和转录抑制，基因转录又受表观遗传学机制调控,然而CD8 T细胞稳态的维持及其分化成为杀伤性T淋巴细胞的表观遗传学调控机制仍然不完全清楚。申请人前期研究发现，转录抑制因子NCoR1不仅在T细胞早期发育过程起关键调节作用，也影响外周CD8 T细胞的数量和激活后的存活；继而进一步研究发现，NCoR1基因缺失对CD8 T细胞稳态维持和免疫应答都有不同程度的影响。基于前期研究结果，本项目拟深入研究NCoR1对CD8 T细胞稳态维持以及免疫应答的调控作用，阐明CD8 T细胞激活过程的表观遗传学调控的分子机制，为免疫治疗和疫苗开发提供理论支撑。

CD8 T细胞受抗原激活后成为杀伤性T细胞，在清除病毒感染和肿瘤细胞过程中起关键作用。该细胞激活过程涉及很多基因的转录激活和转录抑制,基因转录调控受表观遗传学机制调控,然而CD8 T细胞的维持及其分化成为杀伤性T淋巴细胞的表观遗传学调控机制仍然不完全清楚。本项目研究发现NCoR1基因缺失导致记忆性T细胞增多，幼稚性T细胞减少，影响CD8 T细胞稳态维持；NCoR1缺失也导致CD8 T细胞应答显著下降，说明NCoR1在CD8 T细胞应答和激活后存活过程起关键作用。NCoR1与CD8 T细胞免疫应答的促进作用相反， NCoR1对CD4 T细胞应答其负调节作用，NCoR1可以通过调控Th2样TregCD4 T细胞亚群的产生而对记忆性CD8 T细胞维持起调控作用。另外，还发现 CD4和CD8 T细胞的完全激活受ASXL1基因的表观遗传学调控。