Cytotoxic T lymphocytes recognizing conserved peptide epitopes are crucial in the 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) expressed by approximately half of the human population. Herein, 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 CTL responses in both HLA-A*02 and -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 GILGFVFT... More
Cytotoxic T lymphocytes recognizing conserved peptide epitopes are crucial in the 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) expressed by approximately half of the human population. Herein, 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 CTL responses in both HLA-A*02 and -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 1.84Å and comparison with the known GILGFVFTL/HLA-A*02:01 structure revealed that the antigen bound both complexes in near-identical conformation, 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 peptide 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 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 between individuals and populations, and also aid in the design of vaccines.
