title: Promiscuous CTL recognition of viral epitopes on multiple human leukocyte antigens: biological validation of the proposed HLA A24 supertype.
abstract: Multiple HLA class I alleles can bind peptides with common sequence motifs due to structural similarities in the peptide binding cleft, and these groups of alleles have been classified into supertypes. Nine major HLA supertypes have been proposed, including an A24 supertype that includes A*2301, A*2402, and A*3001. Evidence for this A24 supertype is limited to HLA sequence homology and/or similarity in peptide binding motifs for the alleles. To investigate the immunological relevance of this proposed supertype, we have examined two viral epitopes (from EBV and CMV) initially defined as HLA-A*2301-binding peptides. The data clearly demonstrate that each peptide could be recognized by CTL clones in the context of A*2301 or A*2402; thus validating the inclusion of these three alleles within an A24 supertype. Furthermore, CTL responses to the EBV epitope were detectable in both A*2301(+) and A*2402(+) individuals who had been previously exposed to this virus. These data substantiate the biological relevance of the A24 supertype, and the identification of viral epitopes with the capacity to bind promiscuously across this supertype could aid efforts to develop CTL-based vaccines or immunotherapy. The degeneracy in HLA restriction displayed by some T cells in this study also suggests that the dogma of self-MHC restriction needs some refinement to accommodate foreign peptide recognition in the context of multiple supertype alleles.
authors.affiliation: Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Australia. scottb@qimr.edu.au
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Elkington
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Green
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.forename: Sofia M
authors.initials: SM
authors.lastname: Haryana
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Moss
authors.forename: Heather
authors.initials: H
authors.lastname: Dunckley
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Burrows
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000483:Alleles; D002460:Cell Line; D002469:Cell Separation; D002999:Clone Cells; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods*; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D015234:HLA-A Antigens / Q000276:immunology* / Q000378:metabolism*; D059871:HLA-A24 Antigen; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009842:Oligopeptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D009842:Oligopeptides; D014763:Viral Matrix Proteins