A comparative study of HLA binding affinity and ligand diversity: implications for generating immunodominant CD8+ T cell responses

J Immunol. 2009 Feb 1;182(3):1526-32. doi: 10.4049/jimmunol.182.3.1526.

Abstract

Conventional CD8(+) T cell responses against intracellular infectious agents are initiated upon recognition of pathogen-derived peptides presented at the cell surface of infected cells in the context of MHC class I molecules. Among the major MHC class I loci, HLA-B is the swiftest evolving and the most polymorphic locus. Additionally, responses restricted by HLA-B molecules tend to be dominant, and most associations with susceptibility or protection against infectious diseases have been assigned to HLA-B alleles. To assess whether the differences in responses mediated via two major HLA class I loci, HLA-B and HLA-A, may already begin at the Ag presentation level, we have analyzed the diversity and binding affinity of their peptide repertoire by making use of curated pathogen-derived epitope data retrieved from the Immune Epitope Database and Analysis Resource, as well as in silico predicted epitopes. In contrast to our expectations, HLA-B alleles were found to have a less diverse peptide repertoire, which points toward a more restricted binding motif, and the respective average peptide binding affinity was shown to be lower than that of HLA-A-restricted epitopes. This unexpected observation gives rise to new hypotheses concerning the mechanisms underlying immunodominance of CD8(+) T cell responses.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Motifs
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / microbiology
  • CD8-Positive T-Lymphocytes / virology
  • Cytotoxicity, Immunologic* / genetics
  • Genome, Bacterial / genetics
  • Genome, Bacterial / immunology
  • Genome, Viral / genetics
  • Genome, Viral / immunology
  • HLA-A Antigens / genetics
  • HLA-A Antigens / metabolism*
  • HLA-B Antigens / genetics
  • HLA-B Antigens / metabolism*
  • Humans
  • Immunodominant Epitopes / biosynthesis
  • Immunodominant Epitopes / metabolism*
  • Immunodominant Epitopes / physiology
  • Ligands
  • Peptides / immunology
  • Peptides / metabolism
  • Protein Binding / immunology
  • Proteome / genetics
  • Proteome / metabolism

Substances

  • HLA-A Antigens
  • HLA-B Antigens
  • Immunodominant Epitopes
  • Ligands
  • Peptides
  • Proteome