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

Major histocompatability complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs) recognizing Epstein-Barr virus (EBV) latent antigen s 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. T his resistance to immune surveillance is not due to an obvious CTL dys function 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 nuc lear antigens. In the present study we have explored the possibility t hat EBV latent membrane protein 2A (LMP2A), which is often expressed i n many of the EBV-associated malignancies, such as nasopharyngeal carc inoma and Hodgkin's disease tumors, can be endogenously processed thro ugh an alternative, TAP-1- and TAP-2-independent pathway. The data pre sented in this study clearly demonstrate not only that LMP2A can be pr ocessed by a TAP-independent mechanism but also that tumor tells with down-regulated TAP expression can be efficiently recognized by LMP2A-s pecific T cells following infection with recombinant vaccinia virus en coding this protein. We propose that since LMP2A is a membrane protein , it:is directly translocated into the secretory pathway and the proce ssing enzymes present in the endoplasmic reticulum are capable of gene rating the relevant peptide epitopes for MHC binding. The present find ing of TAP-1- and TAP-2-independent presentation of LMP2A epitopes sug gests a novel mechanism for immune targeting of EBV-positive malignanc ies, such as nasopharyngeal carcinoma and Hodgkin's disease tumors.