Processing and Selection of Antigens by the Major Histocompatibility Complex Encoded Peptide Transporter TAP

Abstract

Cytotoxic T lymphocytes (CTL) recognize peptides derived from endogenous proteins in association with HLA class I molecules (reviewed by Townsend and Bodmer 1989). A reliable method to predict which peptide from a given protein of interest could elicit a CTL response would thus be of great practical utility. A large body of data on molecular details of the peptide-HLA class I interaction has accumulated. By means of pool sequencing of naturally processed peptides, allele-specific patterns of highly conserved residues have been discovered at particular positions of these peptides, termed ‘anchor residues’ (reviewed by Rammensee et al. 1995), and have been confirmed by the solution of the three-dimensional structure of the peptide-HLA class I complex (Madden et al. 1991). However, when studies with cell lines defective in class I surface expression led to the discovery of genes for a putative peptide transporter (reviewed by Parham 1990), the latter shown to be located in the membrane of the endoplasmic reticulum (ER), and for subunits of the proteasome complex involved in protein degradation, the generation of antigenic peptides for presentation on HLA class I molecules turned out to be a complex mechanism (Fig. 1; reviewed by Yewdell and Bennink 1992; Howard 1995; Koopmann et al. 1997; Tampé et al. 1997). The function of the peptide transporter, termed TAP (for ‘transporter associated with antigen processing’) has since been confirmed in transfection experiments with these defective cell lines (Spies and DeMars 1991; Powis et al. 1991) and in direct transport experiments that take advantage of trapping of peptides in the ER lumen via glycosylation or binding to major histocompatibility (MHC) molecules using these transfectants (Neefjes et al. 1993; Shepherd et al. 1993; Androlewicz et al. 1993) or using heterologously expressed TAP in insect cells or yeast (Meyer et al. 1994; Urlinger et al. 1997).