MDSC通过PD1/PD-L1信号调控Tfh分化介导血吸虫病免疫应答及免疫病理机制研究

The deposition eggs of schistosoma japonicum in the liver induces host granulomatous reaction and continuous progress in liver immunological damage. That leads to hepatocirrhosis and severe secondary injury or even death. The study found that Tfh in mice infected with schistosoma japonicum can promote the formation of liver granuloma, but the specific regulation mechanism of Tfh is not clear. Previous study found that Tfh and MDSC increased in peripheral blood and spleen of mice infected with schistosoma japonicum, and the expression of PD-1 on Tfh and PD-L1 expression on MDSC were significantly increased, which suggested MDSC may be regulate Tfh differentiation through the PD-1/ PD-L1 signal. In this study, we investigated the role and mechanism of PD-1/PD-L1 in the regulation of Tfh differentiation by using normal and PD-L1-/- mice infected with schistosoma japonicum. The effects of Tfh functional molecules and cytokines by MDSC were detected by flow cytometry, fluorescence quantitative PCR and ELISA. This study will deepen the understanding of the host immune response mechanism of schistosoma japonicum and provide new ideas for the prevention and control of schistosomiasis japonica.

血吸虫卵沉积于肝脏诱发宿主肉芽肿反应及持续进展的肝脏免疫病理损害，导致肝硬化及严重继发损害甚至死亡。滤泡辅助性T细胞（Tfh）促进血吸虫感染小鼠肝脏肉芽肿形成，但关于Tfh调控血吸虫感染宿主免疫应答及免疫病理的机制尚不清楚。我们前期发现血吸虫感染小鼠Tfh表面的PD-1和髓源抑制性细胞（MDSC）表面的PD-L1表达明显增高，具有相关性，提示MDSC可能通过PD-1/PD-L1信号调控Tfh细胞分化。本项目拟在前期研究基础上，以血吸虫感染野生型小鼠及PD-L1-/-小鼠为模型，增强或阻断PD-1/PD-L1信号，检测MDSC对Tfh的功能分子、细胞因子的影响及肝脏肉芽肿的影响，研究PD-1/PD-L1在MDSC调控Tfh分化中的作用及机制。本研究将为Tfh分化机制及其在血吸虫病免疫病理发生发展的作用提供新见解，为以Tfh细胞诱导与功能发挥为靶标的新型干预方法的研究提供科学依据。

日本血吸虫的虫卵沉积于肝脏诱发宿主肉芽肿反应及持续进展的肝脏免疫病理损害，导致肝硬化及严重继发损害甚至死亡。滤泡辅助性T细胞（Tfh）在血吸虫感染宿主免疫应答及免疫病理中发挥重要作用。我们研究发现日本血吸虫感染小鼠中Tfh细胞的比例随感染周期逐渐增多，血吸虫感染小鼠体内MDSC也增高，Tfh表面的PD-1和髓源抑制性细胞（MDSC）表面的PD-L1表达明显增高，具有相关性。体外共培养发现G-MDSC可以通过PD-1/PD-L1信号抑制Tfh细胞的增殖。进一步在日本血吸虫感染PD-L1-/-小鼠及野生型小鼠的研究发现，阻断了PD-1/PD-L1信号，感染早期（5周）Tfh细胞数量受到明显的抑制，说明其受PD-1/PD-L1的抑制，而8周时Tfh细胞数量又增多，说明Tfh不只受PD-1/PD-L1信号调控，还存在其他的调控机制共同影响。PD-1/PD-L1信号阻断后，日本血吸虫感染小鼠肝脏免疫病理加重，虫卵肉芽肿和纤维化程度都加重。本研究阐明了MDSC通过PD-1/PD-L1信号调控Tfh机制及其介导血吸虫感染宿主免疫病理的发生发展，为以Tfh细胞诱导与功能发挥为靶标的新型干预方法的研究提供参考。