基于CEHBP-mTOR-CD4 T 细胞途径增强CD8 T细胞抵抗免疫耗竭的效应及机制研究

项目名称： 基于CEHBP-mTOR-CD4 T 细胞途径增强CD8 T细胞抵抗免疫耗竭的效应及机制研究

项目编号： No.81471624

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： 叶丽林

作者单位： 中国人民解放军第三军医大学

项目金额： 65万元

中文摘要： 治疗性疫苗的进展远落后于国家防控慢性病毒感染疾病的需求，原因之一是慢性感染环境下疫苗新诱导的效应CD8 T细胞产生耗竭。如何提高这些细胞抵抗耗竭的能力成为治疗性疫苗研发的关键科学问题。我们前期的工作证实，体外转输特异性CD4 T细胞能有效对抗CD8 T细胞耗竭，但体外转输用于疫苗不具现实可行性；在前期研究中，我们发现CD4 Epitope based Heterologous Prime-boost (CEHPB)策略大幅提高特异性CD4 T细胞的数量；同时，抑制mTOR信号能提高其分化的质量。基于此，我们提出CEHPB联合mTOR抑制治疗性疫苗新策略，预测数量和质量双重保障的CD4 T细胞能有效对抗疫苗诱导的CD8 T细胞产生耗竭。我们拟采用小鼠慢性LCMV感染模型探讨此策略诱导的CD8 T细胞功能恢复、病毒清除、记忆形成等相关效力及机理，为治疗性疫苗的研发提供技术和理论支撑。

中文关键词： 慢性病毒感染；治疗性疫苗；效应CD8；T细胞；免疫耗竭；CD4；T细胞”帮助“

英文摘要： To date, the progress of therapeutic vaccine development still cannot meet the urgent needs for prevention and control chronic viral infection in our nation. The main reason lies in the exhaustion of vaccine induced de novo effector CD8 T cells by chronic infection caused inhibitory immune microenvironment, resulting in the failure of viral clearance. Thus the key question to be answered for therapeutic vaccine research is how we can improve the capacity of de novo induced effector CD8 T cells in resisting immune exhaustion. One research conducted by our group showed that in vitro adoptively transferred viral specific CD4 T cells can greatly helpeffector CD8 T cells resisting function exhaustion. However such in vitro adoptive transfer strategy cannot be applied to vaccine regiment in reality. But our preliminary data demonstrated thatCD4-Epitope based Heterologous Prime-boost (CEHPB)strategy can dramatically enhance the number of viral specific CD4 T cells; moreover our other data also showed that inhition of mTOR signaling during the differentiation of CD4 T cells can substantially increase the quality of viral specific CD4 T cells. Based on these results, we proposeCEHPB coupled mTOR inhibitionas a novel strategy for therapeutic vaccine research, and hypothesize that CD4 T cells with both good quantity and high quality will effectively protect vaccine de novo induced effector CD8 T cells from exhaustion. To prove our hypothesis, we will utilize LCMV chronic infection model to dissect CD8 T cell function restore, viral clearance and memory reformation, which will lay solid ground for the development of future therapeutic vaccine in viral chronically infected human patients.

英文关键词： chronic viral infection;therapeutic vaccine;effector CD8 T cell;immune exhaustion;CD4 T cellhelp