title: Natural variants of the immunodominant HLA A11-restricted CTL epitope of the EBV nuclear antigen-4 are nonimmunogenic due to intracellular dissociation from MHC class I:peptide complexes.
abstract: EBV isolates from human populations with a high frequency of HLA A11 evade recognition by CTLs specific for an immunodominant A11-restricted epitope derived from the EBV nuclear antigen 4 (EBNA-4). We have previously described four nonimmunogenic variants of this epitope carrying single amino acid substitutions in the anchor residues of the peptide. We have now investigated the antigenicity, A11 binding capacity, endoplasmic reticulum translocation, endogenous processing, and presentation of these variants. The nonimmunogenic peptides were either unable to bind to HLA A11 or formed complexes of significantly lower stability compared with the immunogenic epitope. The latter peptides were produced in relatively large amounts by endogenous processing of EBNA-4 and associated with A11 molecules almost as efficiently as the immunogenic epitope, but the complexes failed to accumulate at the cell surface. The defect was not reversed by incubation of lymphoblastoid cell lines carrying the variant EBV strains at 26 degrees C. CTL lysis of HLA A11 positive targets was achieved by expressing one of the nonimmunogenic peptides through a vaccinia recombinant. However, the amount of peptide required for CTL sensitization exceeded, by at least 30-fold, that required for recognition of the immunogenic epitope. Collectively, these results suggest that complexes containing the nonimmunogenic peptides are formed but are then destroyed intracellularly. Thus, a specialized sorting mechanism seems to contribute in shaping the repertoire of peptides presented to T lymphocytes.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden. elelev@ki.se
authors.forename: V
authors.initials: V
authors.lastname: Levitsky
authors.forename: Q J
authors.initials: QJ
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Levitskaya
authors.forename: M G
authors.initials: MG
authors.lastname: Kurilla
authors.forename: M G
authors.initials: MG
authors.lastname: Masucci
mesh_terms: D002461:Cell Line, Transformed; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D014644:Genetic Variation; D015234:HLA-A Antigens / Q000276:immunology*; D059870:HLA-A11 Antigen; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D010455:Peptides