title: HLA-A2 subtypes are functionally distinct in peptide binding and presentation.
abstract: Nearly half of HLA-A2-positive individuals in African populations have a subtype of HLA-A2 other than the A*0201 allele. We have isolated the common African HLA-A2 subtype genes from Epstein-Barr virus-transformed B cell lines and have established stable class I reduced transfectants expressing these alleles. We have studied the peptide binding and presentation properties of A*0201, A*0202, A*0205, A*0214, and A*6901 by a combination of approaches: assaying direct binding of labeled synthetic peptides, studying the ability of antigen-specific cytotoxic T lymphocytes to recognize peptide-pulsed cells, and sequencing peptide pools and individual ligands eluted from cells. We find that A*0201-restricted peptides can also bind to A*0202 but do not bind strongly to the other alleles in this study. We show that some cytotoxic T lymphocytes can recognize all subtypes capable of binding an antigenic peptide, whereas others are subtype specific. Sequencing of eluted peptides reveals that A*0202 has a similar peptide motif to A*0201, but that A*0205, A*0214, and A*6901 have different motifs. These data strongly support a model in which residue 9 (Phe or Tyr) of the A2/A68/A69 molecules is a critical factor in determining the specificity of the B pocket of the major histocompatibility complex and the position 2 anchor residue of associated peptides. We conclude that a single-amino acid difference in the major histocompatibility complex can be sufficient to cause a dramatic change in the nature of bound peptides, implying that individuals with closely related HLA subtypes may present very different repertoires of antigenic peptides to T cells in an immune response. It is likely to be a general phenomenon that very similar class I subtypes will behave as functionally distinct HLA allotypes.
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
chemical_list: D015789:HLA-A2 Antigen; D008024:Ligands; D010455:Peptides