Valkenburg, Sophie A., Josephs, Tracy M., Clemens, E. Bridie, Grant, Emma J., Nguyen, Thi H. O., Wang, George C., Price, David ![]() ![]() |
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.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Subjects: | Q Science > QR Microbiology > QR355 Virology R Medicine > R Medicine (General) |
Uncontrolled Keywords: | influenza infection human CD8+ T cells T-cell receptor |
Publisher: | National Academy of Sciences |
ISSN: | 1091-6490 |
Date of First Compliant Deposit: | 15 February 2017 |
Date of Acceptance: | 26 February 2016 |
Last Modified: | 02 Nov 2022 10:21 |
URI: | https://orca.cardiff.ac.uk/id/eprint/98326 |
Citation Data
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