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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 (TCR\u03b1\u03b2) cross-reactivity towards IAV variants is needed for a vaccine design. Here, we investigate TCR\u03b1\u03b2 cross-strain recognition across IAV variants within two immunodominant human IAV-specific CD8+ T-cell epitopes, HLA-B*37:01-restricted NP338-346 (B37-NP338) and HLA-A*01:01-restricted NP44-52 (A1-NP44). We find high abundance of cross-reactive TCR\u03b1\u03b2 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-NP338 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.","bibjson":{"author":[{"initials":"EJ","lastname":"Grant","name":"Grant EJ"},{"initials":"TM","lastname":"Josephs","name":"Josephs TM"},{"initials":"L","lastname":"Loh","name":"Loh L"},{"initials":"EB","lastname":"Clemens","name":"Clemens EB"},{"initials":"S","lastname":"Sant","name":"Sant S"},{"initials":"M","lastname":"Bharadwaj","name":"Bharadwaj M"},{"initials":"W","lastname":"Chen","name":"Chen W"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"K","lastname":"Kedzierska","name":"Kedzierska K"}],"identifier":[{"id":"10.1038/s41467-018-07815-5","type":"doi"},{"id":"30575715","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Nat Commun","name":""},"pages":["5427"],"title":"Broad CD8<sub>+</sub> T cell cross-recognition of distinct influenza A strains in humans.","type":"article","url":"http://www.nature.com/articles/s41467-018-07815-5","volume":["9"],"year":[2018]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.35","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/6mtl"},"rcsb":{"url":"https://www.rcsb.org/structure/6mtl"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*44:05 binding \"FEDLRVLSF\" at 1.35&#8491; resolution","unique_chain_count":3}}