The immunodominant influenza A virus M158-66 cytotoxic T lymphocyte epitope exhibits degenerate class I major histocompatibility complex restriction in humans

  • J Virol. 2014 Sep;88(18):10613-23. doi: 10.1128/JVI.00855-14.
Joanna A L Choo  1 ,  Jingxian Liu  2 ,  Xinyu Toh  2 ,  Gijsbert M Grotenbreg  3 ,  Ee Chee Ren  4
Affiliations
  • 1. Department of Microbiology, National University of Singapore, Singapore Immunology Programme, National University of Singapore, Singapore.
  • 2. Singapore Immunology Network, A*STAR, Singapore.
  • 3. Department of Microbiology, National University of Singapore, Singapore Department of Biological Sciences, National University of Singapore, Singapore Immunology Programme, National University of Singapore, Singapore [email protected] [email protected].
  • 4. Department of Microbiology, National University of Singapore, Singapore Singapore Immunology Network, A*STAR, Singapore [email protected] [email protected].
PMID: 24990997 DOI: 10.1128/JVI.00855-14
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.

Importance: 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.