T细胞在胸腺里的正常发育成熟以及外周免疫系统中的免疫反应和记忆应答都受不同的激活性和抑制性转录因子的精细调控。文献报道及我们课题组的初步研究结果表明，抑制性转录因子NCoR1在胸腺发育晚期的T细胞成熟过程和外周T细胞免疫应答过程都起很重要的作用。基于我们过去5年已有的研究积累，本项目将开展如下三个方面的研究：1）深入探索NCoR1在双阳性（DP）胸腺细胞到单阴性（SP）胸腺细胞发育过程中起调控作用的具体细胞发育阶段的作用及其分子机制；2）研究NCoR1基因缺失对CD8+ T细胞免疫应答的影响；3) 阐明NCoR1调控CD8+ T细胞免疫应答的分子机制。本课题的实施，将可能揭示调控胸腺细胞阴性选择过程的新机制，并有利于进一步完善对于胸腺中枢耐受和自身免疫病机理的理解；也将可能阐明调控CD8+ T细胞免疫应答和记忆形成过程的分子机制，从而可能为免疫治疗和疫苗开发提供新的理论基础。

Gene expression profiles change dramatically during the processes of T cell development in thymus and T cell responses to infections in periphery. The changes of gene expression are controlled by distinct sets of transcription factors. Transcription factors can be divided into two categories, transcription activators and transcription repressors. In contrast to transcription activators, the regulatory roles of transcription repressors in T cell development and response remain largely unknown. Nuclear receptor co-repressor 1 (NCoR1), as a transcription repressor, plays an important role in metabolism, cellular development and cancers. Little is known about the molecular mechanisms how NCoR1 regulates T cell development in thymus and responses to antigens in periphery. Our unpublished results based on T-cell-specific NCoR1-knockout mice suggest that NCoR1 plays a critical role in late stage of T cell development in thymus and also in CD8+ T cell responses to microbial infection. This proposal is to further investigate: 1) the molecular mechanisms underlying how NCoR1 controls late stage of T cell development in thymus, 2) how NCoR1 affects the primary and recall responses of CD8+ T cells in periphery; and 3) the molecular mechanisms underlying how NCoR1 regulates CD8+ T cell responses to microbial infections and tumors. These studies will lead to better understanding how central tolerance is established in thymus and how CD8+ T cell responses are regulated in transcription level, thus shedding light on the development of immunotherapies and vaccines.