LAG-3负向调控HCV特异的CD8+T细胞免疫反应及其机制研究

项目名称： LAG-3负向调控HCV特异的CD8+T细胞免疫反应及其机制研究

项目编号： No.81471959

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 瞿小旺

作者单位： 南华大学

项目金额： 62万元

中文摘要： T淋巴细胞耗竭是丙型肝炎病毒(HCV)感染后慢性化的重要机制，淋巴细胞活化基因3（LAG-3）是新近发现的T细胞免疫抑制性受体。本课题组的前期研究工作发现持续抗原刺激下HCV特异性CD8+ T细胞分泌白介素10（IL-10），LAG-3表达上调，T细胞功能下降。结合文献分析，我们推测IL-10可能参与了LAG-3介导的HCV抗原特异的CD8+T细胞免疫反应负向调控，但其作用机制有待进一步研究。本项目拟采用HCV感染的Huh7.5与HCV特异的CD8+T细胞体外共培养模型，通过抗体阻断、基因沉默、过表达、反向染色质免疫共沉淀、基因芯片分析等手段，阐明IL-10介导的LAG-3负向调控HCV特异的CD8+ T细胞免疫反应及其机制；并结合临床样本进行淋巴细胞LAG-3表达与抗病毒治疗后转归的相关性研究。本项目的完成将为HCV感染慢性化的机制及治疗提供新的认识。

中文关键词： 丙型肝炎病毒；淋巴细胞活化基因；3；T细胞耗竭；白介素10

英文摘要： Multiple immune inhibitory receptors expression on HCV specific T cell is the major cause inducing HCV T cell exhaustion. Lymphocyte activation gene 3 (LAG-3) is an important immune regulatory molecule, which show critical role in the regulation of chronic virus infection and which had been identified as an inhibitory receptor. Our previous studies showed increasing expression of LAG-3 and IL-10 secretion by activated HCV specific CD8+T cell with persistent antigen stimulation. Due to LAG-3 expression, the function of HCV specific CD8+T cell decreased, LAG-3 antibody blockade enhance HCV specific CD8+T cell immune response These discoveries showed LAG-3 involved in the regulation of HCV specific CD8+T cell immune response, but the mechanism is not clear According the literature, we hypothesize IL-10 involved LAG-3 mediated negatively regulation on HCV specific CD8+ T cell response. In this study, we use HCV infected Huh7.5 cell and HCV specific CD8+ T cell in vitro co-culture system to explore IL-10 involved LAG-3 mediated negative regulation on HCV specific CD8+ T cell, and demonstrate the regulation mechanism, finally we will analysis the relationship of LAG-3 expression and the outcome of antiviral treatment in chronic HCV infected patients. This study will help us further understanding the mechanism of HCV chronic infection and therapy.

英文关键词： Hepatitis C Virus;Lymphocyte Activation Gene-3;T Cell Exhaustion;Interleukin 10