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 A., Miller, Adrian, Tong, Steven Y.C., Thomas, Paul G., Doherty, Peter C., Rossjohn, Jamie, 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 (116). pp. 4440-4445.

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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 ID: 65211
Item Type: Article (Research - C1)
ISSN: 1091-6490
Keywords: influenza infection, human CD8+T cells, T-cell receptor
Copyright Information: Freely available online through the PNAS open access option. [Open access articles are published under a nonexclusive License to Publish and distributed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license]
Funders: National Health and Medical Research Council (NHMRC), Wellcome Trust (WT), Australian Research Council (ARC)
Projects and Grants: NHMRC 1042662, NHMRC 567122, ARC FT120100416, NHMRC Aboriginal and Torres Strait Islander Health Research Scholarship
Date Deposited: 30 Nov 2020 01:10
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3207 Medical microbiology > 320705 Medical virology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320499 Immunology not elsewhere classified @ 50%
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