Molecular basis for universal HLA A*0201 restricted CD8+ T cell immunity against influenza viruses
Significance Influenza is a rapidly spreading acute respiratory infection that causes profound morbidity and mortality. Established CD8+ T lymphocyte (CTL) immunity directed at conserved viral regions provides protection against distinct influenza A viruses (IAVs) In this study, we show that public T cell receptors (TCRs) specific for the most prominent human CTL epitope (M158 66 restricted by HLA A*0201) are capable of recognizing sporadically emerging variant IAVs. We also identify the structural mechanisms that enable promiscuous TCR recognition in this context. Our analysis suggests that preexisting cross reactive TCRs may limit the spread of newly emerging pandemic IAVs. 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 TCRabs 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+ TCRab 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.
Proceedings of the National Academy of Sciences