Transporter (TAP)‐independent processing of a multiple membrane‐spanning protein, the Epstein‐Barr virus latent membrane protein 2

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Abstract
Antigen presentation to CD8+ cytotoxic T lymphocytes (CTL) usually involves proteolytic cleavage of antigen in the cytosol and the delivery of epitope peptides onto major histocompatibility complex class I molecules in the endoplasmic reticulum (ER) via the heterodimeric peptide transporter TAP1/TAP2. In the few exceptional cases where TAP‐independent presentation of an endogenously expressed protein has been observed, the epitope‐containing domain of the protein either has naturally accessed or has been directed into the ER lumen where it is thought to become susceptible to ER proteases. Here, we describe a novel example of TAP‐independent processing involving the Epstein‐Barr virus (EBV) latent membrane protein LMP2, a multiple membrane‐spanning protein with minimal projection into the ER. Expression of LMP2 in the TAP− T2 cell line, whether from the resident EBV genome or from a recombinant vaccinia virus vector vacc‐LMP2, rendered the cells sensitive to recognition by CTL clones specific for two HLA‐A2.1‐restricted peptide epitopes, LMP2 329–337 or 426–434. Vacc‐LMP2‐mediated sensitization to lysis required expression of the antigen de novo in T2 cells and was blocked by brefeldin A. In the same experiments, two other EBV‐specific CTL epitopes, one derived from LMP2 but restricted through a different HLA allele (A11), the other restricted through A2.1 but derived from a different viral protein (BMLF1), did not display TAP‐independent processing. The results are discussed in relation to the unusual topology of LMP2 in the membrane and the position of the epitope peptides within that structure.

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