Peptide transporter (TAP-1 and TAP-2)-independent endogenous processing of Epstein-Barr virus (EBV) latent membrane protein 2A: implications for cytotoxic T-lymphocyte control of EBV-associated malignancies

Abstract

Major histocompatibility [correction of histocampatability] complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs) recognizing Epstein-Barr virus (EBV) latent antigens play a pivotal role in restricting the proliferation of EBV-infected normal B cells. However, it is now well established that most of the EBV-associated malignancies escape this potent CTL response in vivo. This resistance to immune surveillance is not due to an obvious CTL dysfunction but has been partly attributed to the down-regulation of the peptide transporters, TAP-1 and TAP-2, thus restricting the endogenous loading of MHC class I molecules with peptides derived from viral nuclear antigens. In the present study we have explored the possibility that EBV latent membrane protein 2A (LMP2A), which is often expressed in many of the EBV-associated malignancies, such as nasopharyngeal carcinoma and Hodgkin's disease tumors, can be endogenously processed through an alternative, TAP-1- and TAP-2-independent pathway. The data presented in this study clearly demonstrate not only that LMP2A can be processed by a TAP-independent mechanism but also that tumor cells with down-regulated TAP expression can be efficiently recognized by LMP2A-specific T cells following infection with recombinant vaccinia virus encoding this protein. We propose that since LMP2A is a membrane protein, it is directly translocated into the secretory pathway and the processing enzymes present in the endoplasmic reticulum are capable of generating the relevant peptide epitopes for MHC binding. The present finding of TAP-1- and TAP-2-independent presentation of LMP2A epitopes suggests a novel mechanism for immune targeting of EBV-positive malignancies, such as nasopharyngeal carcinoma and Hodgkin's disease tumors.