重症甲型H1N1流感γδT细胞活化促IL-17高表达的调控机制研究

甲型H1N1流感（简称甲流）病毒引发肺损伤的免疫机制复杂，我们前期工作发现IL-17在甲流肺组织损伤中起重要作用，但IL-17高表达的调控机制未明。最新研究表明：依赖IL-23信号通路激活的γδ T细胞可能是细菌感染IL-17的主要来源。我们也发现甲流小鼠肺泡灌洗液中IL-17升高、γδ T细胞增多。由此提出假设：甲型H1N1流感病毒可通过TLR2激活γδ T细胞，并在IL-23信号通路的介导下引发IL-17的高表达，从而推动肺组织损伤。本项目拟通过研究甲流小鼠肺组织中IL-17+γδT细胞的动态变化、甲型H1N1病毒诱导肺组织γδ T细胞产生IL-17、 IL-23介导的信号通路对肺组织γδ T细胞产生IL-17的调控和IL-17+γδ 细胞在甲流肺损伤发生过程中的作用,来探讨重症甲流肺组织γδT细胞活化促IL-17高表达的调控机制。这一研究将为重症甲流的发病机制和免疫调节剂的研发提供新

The mechanisms that influenza A/H1N1 virus induces lung injury are complex. Our previous studies have demonstrated that IL-17 response mediates acute lung injury induced by influenza A/H1N1 virus [Cell Research (2011) :1-11]. But the source and regulatory mechanism of over-production of IL-17 have not been demonstrated yet. Recently, we observed elevated IL-17 concentration and increased number of γδT lymphocytes in bronchoalveolar lavage fluid of severe influenza A/H1N1 virus infected mice model. In addition, γδT lymphocytes are the main producers of IL-17 after Escherichia coli (E. coli) infection. Recent studies have shown that some human as well as mouse γδT cells express functional TLRs such as TLR2, supporting a role in early responses to bacterial and microbial infections. The presence of IL-23 strongly enhances the effect of TLR2 on γδT cells. So we hypothesize that in severe mice model with influenza A/H1N1 virus infection, IL-17 may be over-produced by γδT lymphocytes via TLR2，and the production is regulated by IL-23 signaling pathway. In order to confirm this hypothesis, we are going to (1) detect the relationship between IL-17 production and and dynamic changes of IL-17+ γδT in the lungs of mice infected with influenza A/H1N1 virus, (2) study the regulatory role of IL-23 signal pathway in the over-production of IL-17 by γδT lymphocytes, and（3）investigate the mechanism that IL-17+γδ T cell mediates acute lung injury with influenza A/H1N1.This study can help us understand more about the mechanisms of IL-17 over-production and regulation in the acute lung injury by influenza A H1N1 virus, and the development of new therapeutic approaches against IL-17 production pathway could be possible.