原发性干燥综合征中CD4+CD161+ T细胞亚群的致病效应及其分子调控机制的研究

The imbalanced autoimmune activity and regulation of CD4+ helper T cell (Treg) play an essential role in the initiation and development of primary Sjögren’s Syndrome (pSS). Recently, we identified the CD4+CD161+ T cells, which included both CD4+CD161+ Teff and CD4+CD161+ Treg subsets, as a polyfunctional pathogenic T cell population actively expressing proinflammatory cytokines such as IL-17A and IFN-gamma. Our study showed that the CD4+CD161+ T cell population was associated with increased inflammation and autoantibody levels in pSS and GITRL was a key cytokine to boost the pathogenic activities of this subset. It is very likely that this CD161+ T cell population is involved in the pathogenesis of pSS. We are going to investigate the proinflammatory phenotypes, pathogenic activities, chemotaxis and regulatory cytokines and signaling pathways of CD4+CD161+ T cells in pSS in a series of studies in cell culture systems, animal models and clinical association analysis by comparing the CD4+CD161+ Tcell subsets and conventional CD4+CD161- T cell subsets from pSS patients. The roles of CD4+CD161+ T cell subset in pSS development will be revealed by this investigation, which will deepen the understanding of immune regulatory mechanism in pSS and may provide novel therapeutic targets for the treatment of pSS.

本课题组最近在原发性干燥综合征（pSS）患者中发现CD4+CD161+T细胞亚群（包括CD4+CD161+Teff和CD4+CD161+Treg）是表达IL-17、IFN-gamma等致炎因子的多功能致病T细胞亚群，并与pSS的炎症活动和自身抗体产生有关，而GITRL是刺激其致炎表型的重要因子。前期结果提示该细胞亚群很可能参与了pSS的致病过程。本课题将对比来源于pSS患者的CD4+CD161+ T细胞亚群与CD161阴性的普通CD4+ T细胞亚群，通过系统的细胞实验、动物实验和患者临床相关性研究，揭示pSS 中CD4+CD161+ T细胞亚群的致炎表型、其对自身反应性B细胞的激活、免疫调节功能、趋化迁移特点及对其调控的因子和信号通路（如GITRL-GITR信号及其下游通路），从而明确该细胞亚群在pSS疾病发展中的作用和调控机制，深化对pSS致病机制的认识，并为pSS的治疗探索新的靶标。

CD161分子被认为是Th17细胞表面标志分子之一，而CD4+CD161+T细胞是表达IL-17、IFN-gamma等致炎因子的多功能致病T细胞亚群，并可能与干燥综合征（SS）的炎症活动和自身抗体产生有关。本课题对CD4+CD161+ T细胞亚群在pSS中表达炎性因子及免疫调节功能等进行了研究，并对其表达的IL-17家族分子与自身抗体水平的相关性进行了分析。明确了在原发性干燥综合征（pSS）等自身免疫病中GITRL通过mTORC1通路促进Th17/Th1反应。根据CD4+CD161+T细胞所受的细胞因子调控机制，探索了针对CD4+CD161+T细胞表达IL-17致病因子的免疫治疗方法。发现运用低剂量 IL-2 治疗可以可促进pSS等自身免疫病患者 Treg扩增而下调 T 细胞向 pTfh/Tfh、 Th17 等致炎 Th 亚群方向的分化， 使 T 细胞免疫稳态得到再平衡，并可实现pSS多个病情指标的改善。本课题组完成了国际首例低剂量 IL-2 治疗pSS的随机双盲安慰剂对照临床研究，并取得了成功，为这种靶向 Treg 分化和稳态的新型免疫治疗方法的临床转化应用，奠定了坚实的科学基础。此外，本课题还发现了多个干燥综合征及相关自身免疫病的生物标志物，有利于干燥综合征及其合并症的诊断。部分成果已申请国家发明专利，具有进一步转化应用的潜力。