CD8+T细胞识别SARS-CoV-2的结构生物学研究

细胞毒性CD8+T细胞介导的免疫应答是维持对SARS-CoV-2长期免疫的关键。申请者前期研究成功鉴定SARS-CoV-2刺突蛋白YLQ表位特异性CD8+T细胞的TCRαβ异源二聚体YC2，且证明YC2能够高亲和力识别HLA-A2递呈的YLQ表位。然而SARS-CoV-2特异性YC2识别YLQ表位的分子结构机制，以及YC2能否交叉识别冠状病毒同源表位等关键科学问题仍不清楚。本项目拟采用X射线晶体学的手段解析YC2、YLQ-HLA-A2、及YC2-YLQ-HLA-A2三元复合物的三维结构，揭示SARS-CoV-2特异性TCR精细识别YLQ表位的分子结构基础及构象变化特征；同时，在生化及细胞水平分析YC2对冠状病毒同源表位的交互作用及免疫应答，探讨YLQ表位特异性CD8+T细胞对冠状病毒广谱免疫的潜力。本项目的完成将为研发SARS-CoV-2长期免疫及广谱免疫的二代疫苗提供结构及理论基础。

The immune response mediated by cytotoxic CD8+ T cells is the key to keep long-term immunity against SARS-CoV-2. In preliminary studies, we had successfully identified the YLQ epitope-specific TCRαβ heterodimer (YC2) from SARS-CoV-2 specific CD8+ T cell, and found that it can recognize the HLA-A2 presented YLQ epitope with high affinity. However, it is still unclear how YC2 recognizes the YLQ epitope of SARS-CoV-2, and whether it can cross-recognize the homo-epitopes of other coronaviruses. In this proposed studies, we will solve the crystal structures of free YC2, YLQ-HLA-A2, and the YC2-YLQ-HLA-A2 ternary complex, which will reveal the molecular structural characteristics of the SARS-CoV-2 specific TCR recognition of YLQ epitope and their conformation changes; Meanwhile, we will investigate the interactions and immune responses of YLQ epitope-specific TCR against the homo-epitopes of other coronaviruses at biochemical and cellular levels to elucidate the broad immunity potential of YLQ epitope-specific CD8+ T cells against coronavirus. This project will provide a structural and theoretical basis for the development of the second-generation vaccine with long-term immunity for SARS-CoV-2 and broad immunity for coronavirus.