We confirm here that CTLs specific for the HLA-B35/B53-presented EBNA1-derived HPVGEADYFEY (HPV) epitope are detectable in the majority of HLA-B35 individuals, and recognize EBV-transformed B lymphocytes, thereby demonstrating that the GAr domain does not fully inhibit the class I presentation of the HPV epitope. In contrast, BL cells are not recognized by HPV-specific CTLs, suggesting that other mechanisms contribute to providing a full protection from EBNA1-specific PD-0332991 chemical structure CTL-mediated lysis. One of the major differences between BL cells and lymphoplastoid cell lines (LCLs) is the proteasome; indeed, proteasomes from BL cells demonstrate far lower chymotryptic
and tryptic-like activities compared with proteasomes from LCLs. Hence, inefficient proteasomal
processing is likely to be the main reason for the poor presentation of this epitope in BL cells. Interestingly, we show that treatments with proteasome inhibitors partially restore the capacity of BL cells to present the HPV epitope. This indicates ALK assay that proteasomes from BL cells, although less efficient in degrading reference substrates than proteasomes from LCLs, are able to destroy the HPV epitope, which can, however, be generated and presented after partial inhibition of the proteasome. These findings suggest the use of proteasome inhibitors, alone or in Amrubicin combination with other drugs, as a strategy for the treatment of EBNA1-carrying tumours. The Epstein–Barr virus (EBV) is a widespread virus that establishes life-long persistent infections in B lymphocytes in the vast majority of human adults. These EBV-infected B cells can proliferate in vitro, giving rise to lymphoblastoid cell lines
(LCLs) that express at least nine latency-associated viral antigens: the nuclear antigens EBNA1 to EBNA6 and the membrane proteins LMP1, LMP2A and LMP2B.1 The proliferation of EBV-infected cells is monitored in vivo by T lymphocytes that specifically recognize viral antigens as peptides derived from the processing of endogenously expressed viral proteins presented on the surface of the target cell as a complex with MHC class I molecules.2 In particular, EBNA3, EBNA4 and EBNA6 (also known as EBNA3A, 3B and 3C) contain immunodominant epitopes for cytotoxic T lymphocyte (CTL) responses over a wide range of HLA backgrounds. In contrast, EBNA2, EBNA5, LMP1 and LMP2 are subdominant targets that are presented in the context of a limited number of HLA restrictions.3–7 Conflicting with previous observations,4,5,8 CTL responses against EBNA1 have also been detected in healthy EBV-seropositive individuals9–13 but, so far, the poor recognition and killing of the target cells that naturally express EBNA1 by EBNA1-specific CTL cultures suggest a poor presentation of EBNA1-derived CTL epitopes.