International Immunology, Vol. 12, No. 3, 281-293,
March 2000
© 2000 Japanese Society for Immunology
A repetitive sequence of Epstein–Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DR-restricted CD4+ T lymphocytes
1 Microbiology and Tumorbiology Center, Karolinska Institute, 17 177 Stockholm, Sweden
2 Department of Immunology, L. Eötvös University, Jávorka S. 14, 2131 Göd, Hungary
3 Blood Centre University Hospital, 22 185 Lund, Sweden
4 Institute of Enzymology, 1518 Budapest, Hungary
5 Department of Immunology, G. D. Searle & Co. Ltd, St Louis, MO 63131-3850, USA
Correspondence to: É. Rajnavölgyi
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 Th 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.
Keywords: human CD4+ T lymphocyte, HLA-DR–peptide interaction, virus-specific immunity
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