共抑制分子TIGIT促进Treg释放FGL2导致脓毒症免疫抑制的机制研究

效应性T细胞功能障碍是脓毒症免疫抑制的重要原因。调节性T细胞（Treg）在调控脓毒症效应性T细胞中起关键作用，但其抑制作用的分子机制尚未阐明。申请者前期研究发现，脓毒症Treg上共抑制分子TIGIT表达显著增高，上调Treg活性。进一步研究发现，TIGIT激动剂使Treg释放更多的免疫抑制因子FGL2。以往研究及预实验结果提示，FGL2可能通过AKT/mTOR通路抑制T细胞糖酵解影响效应性T细胞功能。据此我们推测，脓毒症时高表达TIGIT促进Treg活化并释放FGL2，抑制效应性T细胞内AKT/mTOR介导的糖酵解途径，引起效应性T细胞功能障碍从而导致免疫抑制。本项目拟通过脓毒症患者体内、体外实验及动物模型研究，证明TIGIT通过促进Treg活化释放FGL2，影响效应性T细胞功能；明确FGL2通过抑制糖酵解途径导致效应性T细胞功能障碍的机制，为脓毒症的免疫致病机制及干预靶点提供理论基础。

Effector T cell dysfunction is one of the main reasons for immunosuppression in sepsis. Regulatory T cells (Treg) play a crucial role in regulating effector T cells during sepsis, nonetheless, the molecular mechanism of inhibition is still unclear. We found that the expression of the coinhibitory molecule TIGIT on Treg was significantly upregulated, which resulted in increased Treg activity during sepsis. Further, we demonstrated that TIGIT agonists promote Treg to release more immunosuppressive factor FGL2. Previous studies and preliminary experiments suggested that FGL2 could inhibit T cell glycolysis through AKT/mTOR pathway, which affected the function of effector T cells. Therefore, we speculate that high expression of TIGIT could promote Treg activity to release FGL2, inhibiting glycolysis mediated by AKT/mTOR pathway in the effector T cells, resulting in the dysfunction of effector T cells which leads to the immunosuppression of sepsis. The aim of the project is to verify TIGIT promoting Treg to release FGL2 to affect T cell function, and to determine the mechanism of FGL2 inhibiting glycolysis to induce the dysfunction of effector T cells through in vivo, in vitro studies of septic patients and animal experiment studies. It will provide a theoretical basis for the immunopathogenesis and intervention target of sepsis.