How Selective Is the Transporter Associated with Antigen Processing?

Recognition of foreign and self-antigens by T cells requires the interaction of the T cell receptor with major histocompatibility complex (MHC) class I or class II molecules on the surface of the antigen-presenting cell. The specificity of the interaction is provided by the antigenic peptides that are bound to the MHC molecules. Generally, MHC class I molecules present peptides that are derived from endogenous protein sources, while MHC class II molecules present peptides from exogenous proteins. Many of the peptides presented by class I are derived from cytosolic proteins, and therefore these peptides must cross a lipid bilayer membrane in order to assemble with newly synthesized class I molecules in the lumen of the endoplasmic reticulum (ER) (see Figure 1). In contrast, MHC class II–associated peptides are not subjected to a similar requirement, as internalized antigen in endosomes or lysosomes is topologically equivalent to the class II molecules. To get peptides into the lumen of the ER, the cell has adapted a transport molecule from the large family of transport proteins called ATP-binding cassette (ABC) transporters (for review seeHiggins 1992). Examples of well-characterized ABC transporters include P-glycoprotein (Chen et al. 1986; Gros et al. 1986), the cystic fibrosis transmembrane conductance regulator (CFTR) (Riordan et al. 1989), and the STE 6 transporter in yeast (Kuchler et al. 1989). The peptide transporter, called the transporter associated with antigen processing (TAP), is composed of two homologous proteins termed TAP1 and TAP2 (Trowsdale et al. 1990; Spies et al. 1990; Deverson et al. 1990; Monaco et al. 1990). Together, the TAP1/TAP2 heterodimer forms a transport molecule that conserves the hallmarks of ABC transporters, i.e., the possession of approximately twelve membrane-spanning domains and two hydrophilic ATP-binding domains (see Figure 2). For ABC transporters, the hydrolysis of ATP is coupled to substrate transport.