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

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

  • Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4440-5. doi: 10.1073/pnas.1603106113.
Sophie A Valkenburg 1,  Tracy M Josephs 2,  E Bridie Clemens 1,  Emma J Grant 1,  Thi H O Nguyen 1,  George C Wang 3,  David A Price 4,  Adrian Miller 5,  Steven Y C Tong 6,  Paul G Thomas 7,  Peter C Doherty 8,  Jamie Rossjohn 9,  Stephanie Gras 10,  Katherine Kedzierska 11
Affiliations

Affiliations

  • 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; [email protected] [email protected] [email protected].
  • 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 [email protected] [email protected] [email protected].
  • 11 Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; [email protected] [email protected] [email protected].
PMID: 27036003 DOI: 10.1073/pnas.1603106113
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.

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