title: A repetitive sequence of Epstein-Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DR-restricted CD4(+) T lymphocytes.
abstract: Most human adults carry the Epstein-Barr virus (EBV) and develop immunological memory against the structural and the virus-encoded cellular proteins. The EBV nuclear antigen 6 (EBNA6) elicits cytotoxic T cell responses and it also maintains a persistent antibody response. The majority of sera from EBV-seropositive individuals reacts with a synthetic peptide, p63, comprising 21 amino acids of a repetitive region of EBNA6. CD4(+) T lymphocytes, with specificity for p63, could be recalled from the T cell repertoire of EBV carriers that expressed certain HLA-DR allotypes which were identified as good binders of p63 by an in vitro flow cytometric assay. Analysis of the HLA-DR/p63 interaction by molecular mechanics calculations indicated the presence of multiple overlapping epitopes which were predicted to bind in a HLA-DRB1 allo- and subtype-specific manner. Specific activation of p63-selected long-term CD4(+) T cell cultures resulted in a proliferative response, in the production of IL-2 and in the secretion of high levels of tumor necrosis factor as measured by bioassays. Proliferation and cytokine production of p63-specific T cells could be induced by p63-loaded HLA-DR-matched antigen-presenting cells and by B cells co-expressing relevant HLA-DR molecules and EBNA6. Our results show that peptides of an EBNA6 repeat region induce CD4(+) T cells which can react with EBNA6-carrying cells in many individuals. We suggest that these T(h) cells may be important in conditioning dendritic cells for initiation potent virus-specific immune responses, provide help for EBV-specific B cells, drive IgG isotype switch and support the sustained effector function of memory cytotoxic T lymphocytes.
authors.affiliation: Microbiology and Tumorbiology Center, Karolinska Institute, 17 177 Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Rajnavölgyi
authors.forename: N
authors.initials: N
authors.lastname: Nagy
authors.forename: B
authors.initials: B
authors.lastname: Thuresson
authors.forename: Z
authors.initials: Z
authors.lastname: Dosztányi
authors.forename: A
authors.initials: A
authors.lastname: Simon
authors.forename: I
authors.initials: I
authors.lastname: Simon
authors.forename: R W
authors.initials: RW
authors.lastname: Karr
authors.forename: I
authors.initials: I
authors.lastname: Ernberg
authors.forename: E
authors.initials: E
authors.lastname: Klein
authors.forename: K I
authors.initials: KI
authors.lastname: Falk
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002353:Carrier State / Q000276:immunology; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D007739:L Cells; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D020449:Repetitive Sequences, Amino Acid; D014162:Transfection
chemical_list: D004279:DNA, Viral; D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D007074:Immunoglobulin G; D008222:Lymphokines; D010446:Peptide Fragments