title: The immunodominant influenza A virus M158-66 cytotoxic T lymphocyte epitope exhibits degenerate class I major histocompatibility complex restriction in humans.
abstract: Cytotoxic T lymphocytes recognizing conserved peptide epitopes are crucial for protection against influenza A virus (IAV) infection. The CD8 T cell response against the M158-66 (GILGFVFTL) matrix protein epitope is immunodominant when restricted by HLA-A*02, a major histocompatibility complex (MHC) molecule expressed by approximately half of the human population. Here we report that the GILGFVFTL peptide is restricted by multiple HLA-C*08 alleles as well. We observed that M158-66 was able to elicit cytotoxic T lymphocyte (CTL) responses in both HLA-A*02- and HLA-C*08-positive individuals and that GILGFVFTL-specific CTLs in individuals expressing both restriction elements were distinct and not cross-reactive. The crystal structure of GILGFVFTL-HLA-C*08:01 was solved at 1.84 Å, and comparison with the known GILGFVFTL-HLA-A*02:01 structure revealed that the antigen bound both complexes in near-identical conformations, accommodated by binding pockets shaped from shared as well as unique residues. This discovery of degenerate peptide presentation by both HLA-A and HLA-C allelic variants eliciting unique CTL responses to IAV infection contributes fundamental knowledge with important implications for vaccine development strategies.
  
  
  OBJECTIVE
  The presentation of influenza A virus peptides to elicit immunity is thought to be narrowly restricted, with a single peptide presented by a specific HLA molecule. In this study, we show that the same influenza A virus peptide can be more broadly presented by both HLA-A and HLA-C molecules. This discovery may help to explain the differences in immunity to influenza A virus between individuals and populations and may also aid in the design of vaccines.
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore Immunology Programme, National University of Singapore, Singapore.
authors.forename: Joanna A L
authors.initials: JA
authors.lastname: Choo
authors.affiliation: Singapore Immunology Network, A*STAR, Singapore.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Singapore Immunology Network, A*STAR, Singapore.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Toh
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore Department of Biological Sciences, National University of Singapore, Singapore Immunology Programme, National University of Singapore, Singapore grotenbreg@nus.edu.sg ren_ee_chee@immunol.a-star.edu.sg.
authors.forename: Gijsbert M
authors.initials: GM
authors.lastname: Grotenbreg
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore Singapore Immunology Network, A*STAR, Singapore grotenbreg@nus.edu.sg ren_ee_chee@immunol.a-star.edu.sg.
authors.forename: Ee Chee
authors.initials: EC
authors.lastname: Ren
mesh_terms: D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015236:HLA-C Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000821:virology; D007371:Interferon-gamma / Q000276:immunology; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015236:HLA-C Antigens; C488936:M1 protein, Influenza A virus; D014763:Viral Matrix Proteins; D007371:Interferon-gamma