HBV感染中S1P/S1PRs信号介导肝脏NK/NKT细胞天然免疫应答的作用机制

The liver is an immunological organ with predominant innate immune system. Natural killer (NK) cells and Natural killer T (NKT) cells are lymphocytes of the innate immune system that play major roles in the defense of hepatitis B virus (HBV) infection and liver injury. However, the signals regulating the recruitment, activation, and cytokine production of NK/NKT cells are incompletely understood. We have previously shown that, as an important mediator in regulation of immune function, sphingosine-1-phosphate (S1P)/S1P receptors (S1PRs) signaling were involved in various causes-induced liver injury. In this project, by using HBV transgenic mice that mimic human HBV healthy carriers, coupled with ConA or CCl4-induced inflammation, we will investigate the effects of S1P/S1PRs signaling on NK/NKT cell recruitment,activation, and cytokine production during HBV infection in vivo and in vitro. Understanding the pathophysiological role of S1P/S1PRs signaling in innate immune responses could provide a rational basis for the design of novel therapeutic strategies for HBV infection.

肝脏NK/NKT细胞天然免疫应答是导致HBV感染后发生急慢性肝炎的重要机制，然而感染HBV后，机体是通过哪些途径激活NK/NKT细胞，又是如何招募肝外的NK/NKT细胞进入肝脏并分泌大量细胞因子的，这些问题还需要进一步研究。我们前期工作表明，作为机体免疫调节的重要分子，磷酸鞘氨醇（S1P）及其受体（S1PRs）信号广泛参与了各种病因所致的肝损伤。本项目拟通过免疫刺激剂ConA或化学毒物CCl4诱导HBV转基因小鼠急慢性炎症模型，结合体内和体外实验，探讨S1P/S1PRs信号介导肝脏NK/NKT细胞募集、活化以及分泌细胞因子等方面的作用机制，从而深化我们对病毒性肝炎免疫学发病机制的认识，为乙型肝炎的临床免疫学干预提供新的思路。

肝脏NK细胞天然免疫应答是导致HBV 感染后发生急慢性肝炎的重要机制。本项目通过尾静脉注射HBV1.3质粒或（和）腹腔注射Poly (I:C)，制备病毒性（乙肝）肝炎模型，同时尾静脉注射骨髓来源的间充质干细胞（MSC），观察MSC对肝脏NK细胞生物学活性的调节作用，并分析MSC对肝脏炎症、病毒复制的影响。进而，在体外进行MSC和NK细胞共培养实验，探讨MSC调节NK细胞活性的作用及其机制。本研究结果显示，MSC减轻了Poly (I:C)或HBV诱导的肝损伤，抑制了肝脏NK的募集、活化及杀伤活性。机制上，MSC抑制了S1PR5受体的表达从而抑制了NK细胞的迁移。MSC来源的TGF-β1抑制了肝脏NK细胞上NKG2D受体的表达从而抑制了NK细胞的生物学活性。出乎意料的是，MSC增强了HBV在体内的复制。以上研究结果揭示了MSC对肝脏中NK细胞免疫调节的新作用，为乙型肝炎的临床免疫学干预提供新的理论依据。