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

Valkenburg, Sophie A., Josephs, Tracy M., Clemens, E. Bridie, Grant, Emma J., Nguyen, Thi H. O., Wang, George C., Price, David ORCID: https://orcid.org/0000-0001-9416-2737, Miller, Adrian, Tong, Steven Y. C., Thomas, Paul G., Doherty, Peter C., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Gras, Stephanie and Kedzierska, Katherine 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) , pp. 4440-4445. 10.1073/pnas.1603106113

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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
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

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