Lrch1 调控CD8 T细胞免疫应答功能和机制的研究

CD8 T cells play important roles in antitumor immunity. Identification of new proteins which regulate CD8 T cell responses against tumor is enjoying a growing favor in immunology research.Signaling proteins involved in integrin activation, including ADAP,SKAP55 and DOCK8 were reported to affect cytotoxicity or memory formation of CD8 T cell. Our previous work published in J Exp Med demonstrated that Lrch1 was a new binding protein of Dock8. This new project will further study the role and mechanism of Lrch1 in the regulation CD8 T cell response. Preliminary data revealed that delayed growth of B16F10 melanoma cells and decreased L.monocytogenes load in Lrch1 knock out mice, which was consistent with enhanced cytotoxicity and higher amount of IFNγ and GranzymeB secretion in Lrch1 knock out CD8 T cells. However, little is known about whether and how Lrch1 regulate CD8 T cell activation, proliferation, apoptosis. Because Dock8 regulate memory CD8 T cell formation, we will further examine whether memory CD8 T cell formation would altered by Lrch1 disturbance. This project will provide us a new mechanism in regulation of CD8 T cell responses .

CD8 T细胞在肿瘤免疫中发挥重要作用，寻找调控CD8 T细胞免疫应答的信号分子是研究的热点。其中T细胞内促进整合素活化的信号分子包括ADAP、SKAP55、DOCK8能调控CD8 T细胞的杀伤等效应或记忆功能。申请者近期发表在J Exp Med的工作，发现新型信号蛋白Lrch1结合DOCK8。本申请延续研究Lrch1调控CD8 T细胞免疫应答的功能和机制。预实验利用Lrch1缺失小鼠，发现黑色素瘤生长减慢，更易清除李斯特菌，这与Lrch1抑制CD8 T细胞分泌IFNγ和GranzymeB , 降低杀伤功能相关。目前对Lrch1 在CD8 T 细胞的活化、增殖、凋亡中的作用和分子机制的研究仍是空白。此外，鉴于DOCK8能影响记忆性CD8 T细胞，本申请也将深入探讨Lrch1 调控记忆性CD8 T细胞的形成和机制。本项目期望为增强CD8 T细胞抗肿瘤免疫提供新的靶向分子。

CD8+ T细胞在清除病原和肿瘤过程中发挥着重要作用。TCR信号是CD8+ T细胞充分活化的关键。TCR识别抗原后，跨膜蛋白LAT招募多种信号蛋白并形成“LAT信号小体”，促进下游信号的传导。然而，对影响LAT信号小体形成，从而抑制CD8+ T细胞杀伤功能的信号分子所知甚少。我们的研究发现，LRCH1能够直接结合LAT，抑制LAT的磷酸化以及和GRB2的结合。Lrch1-/-小鼠的CD8+ T细胞的增殖能力和细胞毒性增强，对李斯特菌的感染有更强的清除能力。过继转移的Lrch1-/-CD8+ T细胞对B16-MO5肿瘤的杀伤能力更强。