title: A comparative study of HLA binding affinity and ligand diversity: implications for generating immunodominant CD8+ T cell responses.
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.
authors.affiliation: Department of Theoretical Biology/Bioinformatics, Utrecht University, Utrecht, The Netherlands.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Rao
authors.forename: Ana Isabel C A Fontaine
authors.initials: AI
authors.lastname: Costa
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
authors.forename: Can
authors.initials: C
authors.lastname: Kesmir
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D016680:Genome, Bacterial / Q000235:genetics / Q000276:immunology; D016679:Genome, Viral / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism*; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D020543:Proteome / Q000235:genetics / Q000378:metabolism
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes; D008024:Ligands; D010455:Peptides; D020543:Proteome