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. Epub 2016 Mar 31.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Dogs
  • Female
  • HLA-A2 Antigen* / genetics
  • HLA-A2 Antigen* / immunology
  • Humans
  • Immunity, Cellular*
  • Immunologic Memory / genetics
  • Influenza A virus / genetics
  • Influenza A virus / immunology*
  • Influenza, Human* / genetics
  • Influenza, Human* / immunology
  • Madin Darby Canine Kidney Cells
  • Male
  • Peptides / genetics
  • Peptides / immunology
  • Peptides / pharmacology
  • Receptors, Antigen, T-Cell, alpha-beta* / genetics
  • Receptors, Antigen, T-Cell, alpha-beta* / immunology
  • Vaccination
  • Viral Proteins / genetics
  • Viral Proteins / immunology
  • Viral Proteins / pharmacology

Substances

  • Antigens, Viral
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Peptides
  • Receptors, Antigen, T-Cell, alpha-beta
  • Viral Proteins

Associated data

  • PDB/5HHM
  • PDB/5HHN
  • PDB/5HHO
  • PDB/5HHP
  • PDB/5HHQ