Getting the inside out: the transporter associated with antigen processing (TAP) and the presentation of viral antigen.

The unique role of antigen presentation by major histocompatibility complex (MHC) class I molecules is to enable the immune system to monitor the internal contents of intact cells. Cytotoxic T cells (CTLs) recognize peptide bound to class I molecules on the cell surface, detect virus infection or malignant transformation, and destroy the diseased cell (1). A key piece of information in the understanding of how the information content of the cytosol is transferred to the cell surface by class I was provided by the study of class I-deficient mutant cell lines, which showed that class I molecules bind peptides in the endoplasmic reticulum (ER) before transit to the cell surface (2-4). The same mutant cells enabled the identification of the molecule responsible for transmitting peptides from the cytosol to the ER-the transporter associated with antigen processing (TAP)-a member of the ABC family of transporters (5-7). In the past 2 yr a series of experimental systems from several laboratories has begun to dissect the function of TAP and to address the role of TAP in the overall process of class I-restricted immunity. The combined effects of the peptides transferred by TAP and the peptide-binding capabilities of the class I molecules themselves must allow the immune system to detect the presence of intracellular parasites, and a diverse array of peptides must be able to be presented to optimize the chance of detecting rapidly mutating viruses. At the same time, functional TAP and class I molecules are necessary to select the repertoire of TCRs capable of recognizing foreign peptide (positive selection) and to eliminate those capable of responding to normal self-cells (negative selection). In this commentary we will discuss how the recently accumulated data on the function of TAP and peptide loading in the ER fit this evolutionary role for TAP. The diverse mechanisms that a number of viruses use to subvert the process of class I-restricted antigen presentation impose an additional selective pressure that