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

Sophie A Valkenburg, Tracy M Josephs, E Bridie Clemens, Emma J Grant, Thi H O Nguyen, George C Wang, David A Price, Adrian Miller, Steven Y C Tong, Paul G Thomas, Peter C Doherty, Jamie Rossjohn, Stephanie Gras, Katherine Kedzierska

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37 Citations (Scopus)

Abstract

Memory 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.
Original languageEnglish
Pages (from-to)4440-4445
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number16
DOIs
Publication statusPublished - 19 Apr 2016

Keywords

  • influenza infection
  • human CD8+ T cells
  • T-cell receptor

Cite this

Valkenburg, S. A., Josephs, T. M., Clemens, E. B., Grant, E. J., Nguyen, T. H. O., Wang, G. C., Price, D. A., Miller, A., Tong, S. Y. C., Thomas, P. G., Doherty, P. C., Rossjohn, J., Gras, S., & Kedzierska, K. (2016). Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses. Proceedings of the National Academy of Sciences of the United States of America, 113(16), 4440-4445. https://doi.org/10.1073/pnas.1603106113