负性共刺激分子TIGIT调控糖脂代谢重编程参与CD8记忆T细胞衰老的机制研究

人口老龄化导致衰老相关性疾病发病率和死亡率快速攀升，T细胞衰老是老年人易感肿瘤与感染的重要原因之一。近来发现，记忆T细胞功能下降是免疫衰老的重要特征，发生机制待探索。申请人前期发现，TIGIT是CD8T细胞衰老新型标志物，尤其在衰老记忆T细胞中高表达；更重要的是，TIGIT在衰老记忆T细胞中影响糖脂代谢通路和相关基因表达。据此提出：TIGIT通过调控Akt/mTORC1/2通路，抑制糖酵解，促进脂肪酸氧化，导致衰老记忆CD8T细胞糖脂代谢重编程异常，免疫应答能力下降。本项目拟采用老年小鼠模型，明确TIGIT在记忆T细胞衰老中的作用；通过体内、体外实验阐明糖脂代谢重编程对T细胞衰老的调控机制；利用TIGIT敲除小鼠，探讨TIGIT/Akt/mTORC1/2通路调控糖脂代谢重编程和免疫衰老的分子机制。从代谢途径和信号通路两个层面明确TIGIT介导免疫衰老的机制，为衰老相关疾病的防治提供新靶点。

Population Aging leads to the rapid increase of morbidity and mortality of aging-related diseases. T cell immunosenescence plays a crucial role in susceptibility to cancer and infection in the elderly. Recently, it has been revealed that the defects in memory T cell function is an important feature of immunosenescence, and its mechanism needs to be explored. Our previous studies found that TIGIT is a novel marker of CD8 T cell immunosenescence, especially upregulated in aging memory T cells. More importantly, TIGIT affected the expression of genes related to glycolipid metabolism in aging memory T cells. We hypothesized that TIGIT inhibits glycolysis as well as promoting fatty acid oxidation by regulating the Akt/mTORC1/2 pathway, which leads to abnormal glycolipid metabolism reprogramming and decreased immune response in aging CD8 memory T cells. We aimed to clarify the role of TIGIT in memory T cell senescence with aged mice models, to illustrate the regulatory mechanisms involved in glycolipid metabolic reprogramming disorder on T cell immune senescence in vivo and in vitro; and to explore TIGIT/Akt/mTORC1/2 pathway regulating glycolipid metabolic reprogramming and immune senescence by using TIGIT knockout mice. Our study will reveal the mechanism of TIGIT mediating immunosenescence in the levels of metabolic pathway and signal pathway, providing a new therapeutic target for the treatment and prevention of aging-related diseases.