信号素4A(SEMA4A)调控NKT细胞介导免疫应答的机制研究

信号素与众多免疫细胞上对应的不同受体结合，发挥着调控作用。然而信号素在NKT细胞中的研究一直空白。NKT细胞是固有免疫和适应性免疫之间的“桥梁”，参与影响众多疾病的发生发展。我们前期发现，信号素4A蛋白(SEMA4A)结合于NKT细胞，负向调控其免疫应答，包括抑制其增殖、迁移、活化和免疫效应。通过普筛SEMA4A已知6种受体在NKT细胞中的表达谱，我们发现其中PLEXIN B2受体在NKT细胞中特异性高表达，SEMA4A与NKT细胞的结合及功能发挥依赖于PLEXIN B2。本项目拟从T细胞活化下游和G蛋白偶联信号传导系统进行机制深入研究，并结合小鼠疾病模型和临床样本，分析微环境中SEMA4A水平与NKT细胞功能，及疾病进展之间的相关性。研究结合经典免疫学方法与前沿组学分析，有望明确SEMA4A-PLEXIN B2在NKT细胞免疫应答中的调控作用，为NKT细胞免疫疗法提供潜在靶点。

Semaphorins orchestrate the intricate immune response via interacting with corresponding receptors on different immune cell. However, the expression profile and regulatory role of Semaphorins in NKT cell have not been revealed. NKT cells bridge the innate and adaptive immunity, playing an essential role in regulating the pathogenesis of various diseases..Here we showed, soluble Semaphorin4A (SEMA4A) secreted by other cells such as tumor cells or dendritic cells, could negatively regulate the immune responses of NKT cell, including suppressing the proliferation, migration, activation and immune activity. High PLEXIN B2 expression was observed on NKT cells. Accordingly, we demonstrate the ability of SEMA4A to bind human NKT cells which leads to inhibition of NKT proliferation and cytokine production in a PLEXIN B2 dependent manner. This project intends to further study the molecular mechanism of SEMA4A-PLEXIN B2 axis in modulating NKT cell function from two aspects of signal pathway, including G protein coupled signalling system and TCR activation downstream. Combined with in vivo tumor-bearing mouse model and clinical tumor samples, the relationship between SEMA4A microenvironment, NKT cell dysfunction and tumor progression will be investigated and revealed. We expect to conclude that the SEMA4A-PLEXIN B2 axis has a potential role in NKT cell mediated immune response and is a viable target to develop therapeutics for diseases caused by aberrant signalling in NKT cells.