HLA-A2 subtypes are functionally distinct in peptide binding and presentation.

Abstract

SummaryNearly 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 ofA*0201, A*0202, A*0205, A*0214, and A*6901 by a combination ofapproaches : assaying direct binding oflabeled 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 ofbinding 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) ofthe 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 singleamino 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 .

Identification of Cyclophilin B‐derived Peptides Capable of Inducing Histocompatibility Leukocyte Antigen‐A2‐restricted and Tumor‐specific Cytotoxic T Lymphocytes

“…17,18) For example, HLA-A0201 and -A0207 have a dominant anchor leucine at position 2, and HLA-A0201 shares dominant and strong anchors leucine and valine at position 9 with -A0206 and -A0207, respectively. In addition, these OK-CTL lines possess HLA-A2-restricted and tumor-specific CTL activity toward antigenic epitope(s) expressed on HLA-A0201, -A0206, -A0207 molecules of epithelial cancer cells.…”

Association of Prolonged Survival in HLA-A2+ Progressive Multifocal Leukoencephalopathy Patients with a CTL Response Specific for a Commonly Recognized JC Virus Epitope

“…Since two of the seven PML survivors evaluated in this study did not have detectable JCV-specific CTL, we sought to determine how these individuals might differ from the other subjects in this cohort. Different HLA-A2 subtypes have been shown to be functionally distinct in their ability to bind and present peptide (28). In Caucasians, the A*0201 subtype is expressed in ϳ95% (29), and 49 other subtypes are expressed by the remainder of A2 ϩ individuals.…”

MHC polymorphism under host-pathogen coevolution

“…The high rate of nonsynonymous substitutions within the MHC-peptide binding regions, compared with normal rates in other regions of the MHC Nei 1988, 1989;Parham et al 1989aParham et al , 1989b, suggests that there is Darwinian selection for diversity in MHCpeptide binding. Due to the large population diversity of MHC molecules, different individuals typically mount an immune response against different subsets of the peptides of any particular pathogen (Barouch et al 1995). Pathogens that escape presentation by the MHC molecules of one particular host may thus not be able to escape presentation in another host with different MHC molecules.…”