cMet/FAS偶联模式诱导CD8+ CD28+ T细胞凋亡进而建立肝移植免疫耐受的分子机制研究

T cell activation is a key factor for causing immune rejection and FAS/FASL induced apoptosis is the major reason for this evident. Based on our previous discoveries that HGF-producing cells could prolong allo-grafted liver survive and cMet found expressed in CD8+CD28+T cells that resistant to cell apoptosis, we propose that the CD8+CD28+T cells might exist cMet/FAS Interaction being highly resistant to FAS-mediated apoptosis in allo- or xeno-liver transplantation. In this application, we will clarify how the HGF-cMet-FAS axis regulates cMet/FAS Interaction expressed on CD8+CD28+T cells to induce the CD8+CD28+T cell apoptosis through FAS/FASL pathway and establish immune tolerance in allo-or xeno-liver transplantation.

T细胞持续活化是造成免疫排斥的关键要素。已知FAS/FASL凋亡通路被抑制是导致T细胞持续活化的重要原因。我们前期发现自行纯化的成体肝源性干细胞能够通过释放HGF显著延长异种肝移植排斥模型小鼠的生存时间，且这一效应与CD8+CD28+T细胞中cMet与FAS偶联状态消失、FAS/FASL通路介导凋亡激活有直接关系。鉴于HGF是目前已知唯一的cMet配体，因此，我们首次提出“HGF 结合cMet导致cMet与FAS去偶联，从而启动CD8+CD28+T细胞中FAS/FASL通路凋亡途径并诱导肝移植免疫耐受”这一科学设想。故本项目拟在前期实验基础上，通过体外和在体实验，明确HGF-cMet-FAS轴在诱导CD8+CD28+T细胞凋亡中的作用和分子机制，为建立移植免疫耐受提供新的理论依据。