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

作者：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^*; Kedzierska Katherine^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(16): 4440-4445.

DOI：10.1073/pnas.1603106113

• influenza infection
• human CD8(+) T cells
• T-cell receptor

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(star)0201-M1(58) and the hypervariable HLA-B(star)3501-NP418 antigens. The TCR alpha beta s for HLA-B(star)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(+) TCR alpha beta was selected in HLA-A(star)0201(+) donors responding to M1(58). This public TCR cross-recognized naturally occurring M1(58) variants complexed with HLA-A(star)0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19(+) TCR specificity for the WT and mutant M1(58) peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201(+) individuals. Combined with the high population frequency of HLA-A(star)0201, these data potentially explain the relative conservation of M1(58). 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.

• 出版日期2016-4-19