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CD8(+)T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M158and the hypervariable HLA-B*3501-NP418antigens. The TCR\u03b1\u03b2s for HLA-B*3501-NP418 (+)CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19(+)TCR\u03b1\u03b2 was selected in HLA-A*0201(+)donors responding to M158 This public TCR cross-recognized naturally occurring M158variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19(+)TCR specificity for the WT and mutant M158peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201(+)individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M158 Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.","bibjson":{"author":[{"initials":"SA","lastname":"Valkenburg","name":"Valkenburg SA"},{"initials":"TM","lastname":"Josephs","name":"Josephs TM"},{"initials":"EB","lastname":"Clemens","name":"Clemens EB"},{"initials":"EJ","lastname":"Grant","name":"Grant EJ"},{"initials":"TH","lastname":"Nguyen","name":"Nguyen TH"},{"initials":"GC","lastname":"Wang","name":"Wang GC"},{"initials":"DA","lastname":"Price","name":"Price DA"},{"initials":"A","lastname":"Miller","name":"Miller A"},{"initials":"SY","lastname":"Tong","name":"Tong SY"},{"initials":"PG","lastname":"Thomas","name":"Thomas PG"},{"initials":"PC","lastname":"Doherty","name":"Doherty PC"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"K","lastname":"Kedzierska","name":"Kedzierska K"}],"identifier":[{"id":"10.1073/pnas.1603106113","type":"doi"},{"id":"27036003","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Proc. 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