γδT细胞在肝纤维化中的保护作用及机制研究

Hepatic fibrosis is a chronic liver disease and is characterized by excessive deposition of extracellular matrix, which is the leading cause of liver cancer and serious threat to the health of human being. IL-17A and IFN-γ produced by γδT cells play a prominent role in maintaining overall liver homeostasis. Our previous study has demonstrated that γδT cells play an important role in inhibiting liver fibrosis by increasing the expression of NKG2D and FasL contributing to induce activated hepatic stellate cells apoptosis, and regulate cytokine profiles of αβT cells，but the subsets of γδT cells and the mechanism of the protective role that inhibits the development of liver fibrosis are still not clear. In the current proposal, we will use CCl4 induced liver fibrosis to explore the role and the mechanism of γδT cell subsets in the liver fibrosis. In this proposal, we will address our scientific questions with the following specific aims: 1) Role of γδT subsets in CCl4 induced liver fibrosis; 2) The mechanism of γδT cells exerting protective role in liver fibrosis; 3) Was this protective role of γδT cells regulated by liver immune cells? We expect to illustrate the key molecular and mechanism of the protective role of the γδT cells and the cross talk between γδT cells and liver immune cells in the progress of liver fibrosis. Our study will lay a solid foundation for the application of γδT cells in immunotherapy against liver fibrosis.

肝纤维化是一种以细胞外基质重塑为特征的慢性肝损伤，随着病程进展可发展为肝硬化甚至肝癌，严重危害人类健康。γδT细胞通过产生IL-17A及IFN-γ介导的免疫调控在维持肝脏稳态中发挥着重要功能。此外，我们前期研究表明γδT细胞能够抑制肝纤维化进展，通过上调NKG2D及FasL直接杀伤促纤维化的肝星状细胞，还可调节αβT细胞因子表达谱，但其发挥抗纤维化作用的细胞亚群及机制尚不明确。本项目拟应用CCl4诱导的肝纤维化小鼠模型系统地研究γδT在肝纤维化中的保护作用及分子机制，关键科学问题：1）γδT细胞哪个亚群在CCl4诱导的肝纤维化中发挥保护作用？2）γδT细胞亚群抑制肝纤维化的分子机制是什么？3）γδT细胞抑制肝纤维化的效应是否受到其他免疫细胞调控？本研究将阐明肝纤维化过程中γδT各亚群细胞发挥效应的关键分子及其与肝脏免疫细胞的相互调控作用，为γδT细胞应用于临床肝纤维化治疗奠定理论基础。

肝纤维化是由多种慢性肝损伤引起的自愈过程，其特点是肝星状细胞活化及大量细胞外基质的沉积，导致肝组织中结缔组织的异常增殖。有研究表明γδT细胞在肝纤维化发生发展中起重要作用，但对其发挥抗纤维化效应的具体机制仍不明确。因此，我们通过利用TCRδ-/-小鼠过继回输不同基因缺陷的γδT细胞，证明γδT细胞来源的IFN-γ 在肝纤维化中介导保护作用，并可以抑制CD4+T 分泌促纤维化的IL-17。另一方面，γδT细胞可以通过Fas-FasL的机制诱导火花的肝星状细胞凋亡。此外，我们的研究结果表明在肝纤维化模型中，γδT 细胞中mTORC2信号被激活，从而调控γδT 细胞趋化迁移至纤维化的肝脏中，我们进一步明确肝脏中浸润性巨噬细胞分泌的IL-1β可上调γδT细胞CXCR3的表达，从而介导INF-γ+ γδ T细胞浸润至纤维化的肝脏中发挥保护作用。因此，我们的研究结果进一步阐明了γδT细胞浸润至纤维化肝脏中的机制，能够为肝纤维化疾病的治疗提供新的靶点。