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.
- influenza infection
- human CD8+ T cells
- T-cell receptor
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
(16), 4440-4445. https://doi.org/10.1073/pnas.1603106113