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Article: Molecular basis for universal HLA-A*0201–restricted CD8+ T-cell immunity against influenza viruses

TitleMolecular basis for universal HLA-A*0201–restricted CD8+ T-cell immunity against influenza viruses
Authors
KeywordsHuman CD8+ T cells
Influenza infection
T-cell receptor
Issue Date2016
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, v. 113, n. 16, p. 4440-4445 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/241222
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883

 

DC FieldValueLanguage
dc.contributor.authorValkenburg, Sophie A.-
dc.contributor.authorJosephs, Tracy M.-
dc.contributor.authorClemens, E. Bridie-
dc.contributor.authorGrant, Emma J.-
dc.contributor.authorNguyen, Thi H.O.-
dc.contributor.authorWang, George C.-
dc.contributor.authorPrice, David A.-
dc.contributor.authorMiller, Adrian-
dc.contributor.authorTong, Steven Y.C.-
dc.contributor.authorThomas, Paul G.-
dc.contributor.authorDoherty, Peter C.-
dc.contributor.authorRossjohn, Jamie-
dc.contributor.authorGras, Stephanie-
dc.contributor.authorKedzierska, Katherine-
dc.date.accessioned2017-05-26T03:37:08Z-
dc.date.available2017-05-26T03:37:08Z-
dc.date.issued2016-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2016, v. 113, n. 16, p. 4440-4445-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/241222-
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.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectHuman CD8+ T cells-
dc.subjectInfluenza infection-
dc.subjectT-cell receptor-
dc.titleMolecular basis for universal HLA-A*0201–restricted CD8+ T-cell immunity against influenza viruses-
dc.typeArticle-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.1603106113-
dc.identifier.pmid27036003-
dc.identifier.scopuseid_2-s2.0-84964331011-
dc.identifier.volume113-
dc.identifier.issue16-
dc.identifier.spage4440-
dc.identifier.epage4445-
dc.identifier.eissn1091-6490-

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