In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 16 ( 2016-04-19), p. 4440-4445
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-M1 58 and the hypervariable HLA-B*3501-NP 418 antigens. The TCRαβs for HLA-B*3501-NP 418 + CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP 418 -specific CTL sets. Conversely, a dominant public TRAV27/TRBV19 + TCRαβ was selected in HLA-A*0201 + donors responding to M1 58 . This public TCR cross-recognized naturally occurring M1 58 variants complexed with HLA-A*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*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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1603106113
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2016
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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