iNKT细胞抑制CD8+T细胞记忆分化及其作用机制

了解调控CD8+T细胞记忆分化对肿瘤免疫治疗的开发至关重要。已知外源合成抗原α-Galcer活化的iNKT细胞增强CD8+T细胞的免疫效应，并提高记忆CD8+T细胞的形成。我们前期研究发现，在癌症等缺乏iNKT细胞外源脂质抗原情况下，iNKT细胞通过与CD8+T细胞相互作用增强CD8+T细胞的效应功能，但iNKT细胞能否调节CD8+T细胞记忆分化尚不清楚。预实验结果表明：在无外源脂质抗原情况下，iNKT细胞抑制CD8+T细胞记忆分化，并发现iNKT细胞依赖CD8+T细胞表面的CD1d分子，抑制CD8+T细胞记忆分化，提示iNKT细胞被CD8+T细胞呈递的内源抗原激活进而抑制CD8+T细胞记忆分化。本项目拟通过敲除iNKT细胞IFN-γ揭示iNKT细胞抑制CD8+T细胞的记忆分化的作用机制，并通过肿瘤模型加以验证，为癌症、病毒感染的免疫治疗提供新思路。

Understanding the mechanisms that regulate the memory CD8+T cell differentiation is crucial for development of tumor immunotherapy. It is well known that iNKT cells significantly enhance CD8+T cell immune response, as well as promote memory CD8+T cell formation responding to exogenous synthetic lipid antigen,α-Galcer. In previous study, we have found that iNKT cells directly interact with CD8+T cells to promote the effector functions of CD8+T cells in the absence of exogenous lipid antigens, such as in cancer. However, whether iNKT cells can regulate the memory differentiation of CD8+T cells remains unclear. Our preliminary results show that iNKT cells inhibit memory differentiation of CD8+T cells. We also found that iNKT cells inhibited CD8+T cell memory differentiation depending on the expression of CD1d on CD8+T cells. It indicates that CD8+T cells can present endogenous lipid antigens to activate iNKT cells, which in turn inhibit CD8+T cell memory differentiation. Current project intends to further explore the mechanism of iNKT cells inhibiting the memory differentiation of CD8+T cells through knockout of IFN-γ in iNKT cells, and verify it in tumor model, This study can provide a new insight for immunotherapy of cancers and infectious disease.