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dc.contributor.authorValkenburg, Sophie A
dc.contributor.authorJosephs, Tracy M
dc.contributor.authorClemens, E Bridie
dc.contributor.authorGrant, Emma J
dc.contributor.authorNguyen, Thi HO
dc.contributor.authorWang, George C
dc.contributor.authorPrice, David A
dc.contributor.authorMiller, Adrian
dc.contributor.authorTong, Steven YC
dc.contributor.authorThomas, Paul G
dc.contributor.authorDoherty, Peter C
dc.contributor.authorRossjohn, Jamie
dc.contributor.authorGras, Stephanie
dc.contributor.authorKedzierska, Katherine
dc.description.abstractMemory 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-M158 and the hypervariable HLA-B*3501-NP418 antigens. The TCRαβs 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+ TCRαβ was selected in HLA-A*0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, 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.
dc.publisherNational Academy of Sciences
dc.relation.ispartofjournalProceedings of the National Academy of Sciences of the United States of America
dc.subject.fieldofresearchImmunology not elsewhere classified
dc.titleMolecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorMiller, Adrian

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