髓质区CD4单阳性T细胞发育中的阴性选择、nTreg分化及功能成熟研究

CD4 single-positive (SP) thymocyte development in the medulla represents a critical stage in T cell development. This project is focused on such medullary events as negative selection, nTreg differentiation and functional maturation to understand several important issues. Firstly, what is the mechanism that prevents the premature emigration of thymocytes which are not fully selected? and what is the role of CCR2-mediated retention signal for the regulated emigration? Secondly, How does the ectopic expression of CD4 promoter-driven Id1 transgene substitute for the CD28-mediated co-stimulatory signal in the promotion of nTreg differentiation? Thirdly, how is the Th2 bias generated for CD4 SP thymocytes and CD4+ recent thymic emigrants? What role does IL-27 derived from thymic DCs play in the generation of such a bias? and what is its physiological and pathological relevance? Lastly, how is the integrity of the postnatal thymic epithelium maintained? and what is the contribution of Cbx4 to the proper maintenance. Answers to these questions should allow better understanding of mechanisms regulating T cell development and help the strategic design of medical intervention in situations like autoimmunity and immunodeficiency.

髓质区单阳性T细胞发育代表着胸腺T细胞发育的一个关键性阶段。围绕阴性选择、nTreg分化和功能成熟这些髓质区重大事件，本项目致力于回答以下问题：1）机体借助怎样的机制保证惟有那些经过充分阴性选择的胸腺细胞方能输出至外周？CCR2介导的滞留信号在其中发挥怎样的作用？2）CD4启动子驱动的Id1转基因表达如何模拟CD28介导的共刺激信号促进nTreg分化？3）CD4单阳性胸腺细胞和新近从胸腺输出的CD4+ T细胞的Th2偏向是如何形成？DC来源的IL-27在其中发挥怎样的作用？这种偏向有何生理与病理意义？4）胸腺上皮结构，尤其是髓质区上皮结构的完整性是如何维系的？Cbx4分子对此的贡献是什么？研究结果将有助于深化对T细胞发育调控的认识，并有望为自身免疫、免疫缺陷等病理状况的医学干预提供新的思路。

髓质区单阳性T细胞发育代表着胸腺T细胞发育的一个关键性阶段。本项目致力于解析调控胸腺细胞功能成熟、nTreg分化、胸腺迁出、迁出细胞氧化应激响应和胸腺上皮细胞结构维系的分子机制，主要发现如下：1）CCR2信号通过调控S1P1表达和增强细胞非定向运动促进成熟胸腺细胞迁出到外周，同时CCR2介导的细胞非定向运动增加了自身反应T细胞与对应自身抗原的接触，从而促进阴性选择；2）Id分子通过增强TCR信号转导促进胸腺nTreg细胞分化，而对iTreg产生Id分子则呈现明显的双向作用；3）胸腺DC表达的IL-27能够通过负向调控Stat1的活化，诱导新产生的胸腺细胞发生表观遗传改变，从而使其功能发生Th1偏离，IL-27信号缺失令新生T细胞获得更强的IFN-产生能力，这种特性使个体对自身免疫的易感性显著增加；4）氧化应激条件下，PRAK活化诱导的线粒体自噬对新近迁出胸腺细胞在外周的存活是必须的，类似的机制可能也参与了转移肿瘤细胞存活的调控；5）Cbx4通过抑制p21的表达在成年胸腺上皮结构维持中发挥重要作用，其缺失导致上皮细胞前体的耗竭和胸腺器官过早退化。上述结果有助于深化对T细胞发育调控的认识，并有望为自身免疫、免疫缺陷、肿瘤等病理状况的医学干预提供新的思路。