Targeting Epstein-Barr virus nuclear antigen 1 (EBNA1) through the class II pathway restores immune recognition by EBNA1-specific cytotoxic T lymphocytes: evidence for HLA-DM-independent processing.
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all malignancies associated with EBV and there is now convincing evidence to suggest that EBNA1 is not recognized by MHC class I-restricted cytotoxic T lymphocytes (CTL). The lack of recognition of EBNA1 has been attributed to a cis-acting inhibitory effect of glycine-alanine repetitive (G-Ar) sequences on the endogenous processing of this antigen through the class I pathway. In the present study we have explored the possibility of targeting EBNA1 through an alternative mechanism using the MHC class II pathway. Using purified EBNA1 protein, we demonstrate here that CD4+ CTL can efficiently recognize EBV-transformed B cells and Burkitt's lymphoma cells following exogenous sensitization with this antigen, and this immune recognition is not affected by the G-Ar domain within EBNA1. Analysis of the processing mechanism revealed that intracellular loading of class II molecules with an EBNA1 epitope occurs through an HLA-DM-independent pathway. These results highlight a novel mechanism for immune recognition of EBNA1 and also demonstrate that the G-Ar-mediated protection from processing can be overridden if this antigen is presented through the class II pathway.
Khanna
R
R
Queensland Institute of Medical Research, Bancroft Centre, Brisbane, Australia.
Burrows
S R
SR
Steigerwald-Mullen
P M
PM
Moss
D J
DJ
Kurilla
M G
MG
Cooper
L
L
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002460:Cell Line; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism*; D006681:HLA-D Antigens / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D000949:Histocompatibility Antigens Class II