Differential immunogenicity of Epstein-Barr virus (EBV) encoded growth transformation-associated antigens in a murine model system.
The strong immunosurveillance of humans against EBV transformed immunoblasts, mediated by CD8+ cytotoxic T cells, is based on the recognition of peptides derived from eight of the nine growth transformation-associated proteins, the nuclear antigens EBNA2-6 and the membrane proteins LMP1, -2A and -2B. The ninth protein, EBNA1, required for maintenance of the viral episomes, and expressed in a cell phenotype independent manner, has not been found to generate a cytotoxic lymphocyte (CTL) response in humans. We tested whether EBNA1 has a similar immunologically privileged status in a species that has not encountered the virus in nature, the mouse. Non-immunogenic murine mammary carcinoma cells were transfected with the appropriate viral gene. Rejection responses were assayed in syngeneic mice following repeated immunisation with irradiated cells. Previously, we found that LMP1 expression in S6C, a murine mammary carcinoma of ACA (H-2f) origin, induces high rejectability, whereas corresponding EBNA1 transfectants remained non-immunogenic. In order to test whether this finding could be reproduced on another MHC class 1 background, we expressed LMP1 and EBNA1 in another non-immunogenic mammary carcinoma, SBfnHd of CBA (H-2k) origin. LMP1 but not EBNA1 transfectants were immunogenic in this system. In order to investigate whether other growth transformation-associated EBV proteins were immunogenic in the mouse, we also transfected the S6C cells with EBNA4, EBNA5, LMP2A and -2B. All four proteins induced strong rejection reactions. These findings are fully consistent with corresponding findings in the human system. They also show that the immunologically privileged status of EBNA1 is not due to some peculiarity of the long-standing co-existence between EBV and the human species, nor to any specific features of the human MHC class I system. They are consistent with the suggestion that EBNA1 may not be properly processed and/or transported, due to specific features of the protein itself.
Trivedi
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P
Microbiology and Tumour Biology Centre (MTC), Karolinska Institute, Stockholm, Sweden.
Winberg
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Klein
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D000818:Animals; D000956:Antigens, Viral / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D014162:Transfection; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000032:analysis / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins