Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3010, Australia.
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Nat Commun. 2018 Dec 21;9(1):5427. doi: 10.1038/s41467-018-07815-5.
Newly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8 T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding of T-cell receptor (TCRαβ) cross-reactivity towards IAV variants is needed for a vaccine design. Here, we investigate TCRαβ cross-strain recognition across IAV variants within two immunodominant human IAV-specific CD8 T-cell epitopes, HLA-B37:01-restricted NP (B37-NP) and HLA-A01:01-restricted NP (A1-NP). We find high abundance of cross-reactive TCRαβ clonotypes recognizing distinct IAV variants. Structures of the wild-type and variant peptides revealed preserved conformation of the bound peptides. Structures of a cross-reactive TCR-HLA-B37-NP complex suggest that the conserved conformation of the variants underpins TCR cross-reactivity. Overall, cross-reactive CD8 T-cell responses, underpinned by conserved epitope structure, facilitates recognition of distinct IAV variants, thus CD8 T-cell-targeted vaccines could provide protection across different IAV strains.
新出现的和疫苗不匹配的甲型流感病毒（IAV）由于抗体介导的免疫作用极小，导致病毒迅速在全球范围内传播。在这种情况下，已建立的 CD8 T 细胞可以减轻疾病的严重程度。然而，由于免疫原性 IAV 衍生 T 细胞肽内会零星出现突变，因此需要了解 T 细胞受体（TCRαβ）对 IAV 变体的交叉反应性，以进行疫苗设计。在这里，我们研究了两个免疫显性的人类 IAV 特异性 CD8 T 细胞表位中 IAV 变体之间的 TCRαβ 交叉株识别，HLA-B37:01 限制性 NP（B37-NP）和 HLA-A01:01 限制性 NP（A1-NP）。我们发现大量的交叉反应性 TCRαβ克隆型识别不同的 IAV 变体。野生型和变体肽的结构揭示了结合肽的保留构象。交叉反应性 TCR-HLA-B37-NP 复合物的结构表明，变体的保守构象支持 TCR 交叉反应性。总的来说，受保守表位结构支撑的交叉反应性 CD8 T 细胞反应有助于识别不同的 IAV 变体，因此针对 CD8 T 细胞的疫苗可以在不同的 IAV 株中提供保护。
