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Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4440-5. doi: 10.1073/pnas.1603106113. Epub 2016 Mar 31.

Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses.

Author information

1
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
2
Infection and Immunity Program, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;
3
Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
4
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
5
Indigenous Research Network, Griffith University, Brisbane, QLD 4111 Australia;
6
Menzies School of Health Research, Darwin, NT 0810, Australia;
7
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105;
8
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105; pcd@unimelb.edu.au stephanie.gras@monash.edu kkedz@unimelb.edu.au.
9
Infection and Immunity Program, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
10
Infection and Immunity Program, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia pcd@unimelb.edu.au stephanie.gras@monash.edu kkedz@unimelb.edu.au.
11
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; pcd@unimelb.edu.au stephanie.gras@monash.edu kkedz@unimelb.edu.au.

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-M158and the hypervariable HLA-B*3501-NP418antigens. 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 M158variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19(+)TCR specificity for the WT and mutant M158peptides, 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.

KEYWORDS:

T-cell receptor; human CD8+ T cells; influenza infection

PMID:
27036003
PMCID:
PMC4843436
DOI:
10.1073/pnas.1603106113
[Indexed for MEDLINE]
Free PMC Article

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