PDF(Pubmed)
Abstract：
The individual HLA-related susceptibility to emerging viral diseases such as COVID-19 underscores the importance of understanding how HLA polymorphism influences peptide presentation and T cell recognition. Similar to HLA-A*0101, which is one of the earliest identified HLA alleles among the human population, HLA-A*2601 possesses a similar characteristic for the binding peptide and acts as a prevalent allomorph in HLA-I. In this study, we found that, compared with HLA-A*0101, HLA-A*2601 individuals exhibit distinctive features for the T cell responses to SARS-CoV-2 and influenza virus after infection and/or vaccination. The heterogeneous T cell responses can be attributed to the distinct preference of HLA-A*2601 and HLA-A*0101 to T cell epitope motifs with negative-charged residues at the P1 and P3 positions, respectively. Furthermore, we determined the crystal structures of the HLA-A*2601 complexed to four peptides derived from SARS-CoV-2 and human papillomavirus, with one structure of HLA-A*0101 for comparison. The shallow pocket C of HLA-A*2601 results in the promiscuous presentation of peptides with \"switchable\" bulged conformations because of the secondary anchor in the median portion. Notably, the hydrogen bond network formed between the negative-charged P1 anchors and the HLA-A*2601-specific residues lead to a \"closed\" conformation and solid placement for the P1 secondary anchor accommodation in pocket A. This insight sheds light on the intricate relationship between HLA I allelic allomorphs, peptide binding, and the immune response and provides valuable implications for understanding disease susceptibility and potential vaccine design.
摘要：
个体HLA对新出现的病毒性疾病如COVID-19的易感性强调了理解HLA多态性如何影响肽呈递和T细胞识别的重要性。类似于HLA-A*0101，这是人类中最早鉴定的HLA等位基因之一，HLA-A*2601具有类似的结合肽特征，并在HLA-I中充当普遍的同种异体。在这项研究中,我们发现,与HLA-A*0101相比,HLA-A*2601个体在感染和/或接种疫苗后对SARS-CoV-2和流感病毒的T细胞应答表现出独特的特征.异质T细胞应答可归因于HLA-A*2601和HLA-A*0101对P1和P3位置带负电荷残基的T细胞表位基序的不同偏好。分别。此外，我们确定了与SARS-CoV-2和人乳头瘤病毒衍生的四种肽复合的HLA-A*2601的晶体结构，与HLA-A*0101的一个结构进行比较。HLA-A*2601的浅袋C导致肽的混杂呈现，由于中间部分的次级锚定，因此具有“可切换的”凸起的构象。值得注意的是,带负电荷的P1锚和HLA-A*2601特异性残基之间形成的氢键网络导致P1二级锚在口袋A中的“封闭”构象和固体放置。这一见解揭示了HLAI等位基因同种异型之间的复杂关系，肽结合，和免疫反应，并为了解疾病易感性和潜在的疫苗设计提供了有价值的启示。
