不同HLA超级型人群对流感病毒的交叉CD8+ T细胞反应及机制研究

Since its first identification in April 2009, the 2009 pandemic influenza A virus H1N1 (2009 pH1N1) has given rise to the first pandemic in the twenty-first century. During the following seasons, the prevalence of 2009 pH1N1 has continuously been reported, especially in the past 2012-2013 season, resulting in deaths in China and other countries. Human leukocyte antigen (HLA)-restricted CD8+ T cells are illuminated to have a pivotal role in anti-influenza virus immunity. However, the diversity of HLA alleles among humans complicates the research on virus-specific cellular immunity. An ideal T cell epitope-based vaccine would cover a broad spectrum of epitope antigens to be presented by most, if not all, of the HLAs. Previouly, we have identified cross-HLA allele T cell responses against the influenza A virus peptides among both HLA-A11+ and HLA-A24+ supertype populations. In this study, we will further investigate the characterization and mechanism of the cross-HLA allele T cell responses to influenza virus and determine their roles in the anti-virus protection. Furthermore, we will perform the X-ray crystallographic strategy to determine the structural basis of the cross-HLA allele T cell responses, based on which the influenza peptides will be modified for antigenic improvement. Our findings will illuminate the mechanism of the cross-allele T cell responses against influenza A viruses and are beneficial for the development of a T cell epitope-based vaccine applied in a broader population.

自2009年以来，甲型H1N1流感病毒在全球不同国家不断流行，在2012-2013季更成为我国北方地区的季节性流感之一。特异性T细胞在抗流感感染中发挥重要的免疫保护作用。而人群中HLA基因存在很高的多态性，这使得检测不同HLA分型人群的流感特异性T细胞免疫反应，以及研发针对广泛HLA分型的T细胞表位疫苗成为研究的难点。申请人对2009甲型流感病毒上可能存在的特异性T细胞表位多肽进行了筛选和鉴定，并用多种方法鉴定到在HLA-A24+和HLA-A11+个体能够产生交叉T细胞免疫反应的表位。本研究拟进一步探讨不同HLA超级型人群对H1N1流感病毒的交叉CD8+ T细胞反应的机制以及在抗流感保护力中发挥的作用；另一方面，通过X射线晶体学手段研究不同HLA分子交叉呈递相同流感表位的结构学基础。为进一步的针对广泛人群的T细胞免疫水平检测以及T细胞疫苗的研发提供材料和理论基础。

特异性T细胞在抗流感感染中发挥重要的免疫保护作用。而人群中HLA基因存在很高的多态性，这使得检测不同HLA分型人群的流感特异性T细胞免疫反应，以及研发针对广泛HLA分型的T细胞表位疫苗成为研究的难点。在本项目的资助下，首先以HLA-A3超级型等人群为研究对象，通过一系列细胞免疫学、结构免疫学等方法，对人群针对H1N1流感病毒、H7N9禽流感病毒感染及相关疫苗的CD8+ T细胞反应的机制进行了系统而深入研究；我们发现HLA-A*33个体与HLA-A*11个体耐受流感病毒多肽突变的能力不同。感染过H1N1流感病毒的HLA-A*11个体，对H7N9多肽的识别能力不高；而感染过H1N1流感病毒的HLA-A*33个体结合和识别H7N9突变多肽的能力更强。这就表明季节性流感病毒和禽流感病毒之间的T细胞免疫交叉反应受到个体本身HLA I分型的影响。这为进一步的针对广泛人群的T细胞免疫水平检测以及T细胞疫苗的研发提供材料和理论基础。同时，在本项目中，我们还对中东呼吸综合征病毒及其他新发和再发病毒的分子流行病学和T细胞识别分子机制进行了研究，对于新发突发重大病毒性疾病的防控和诊治具有重要指导意义。