Down-regulation of MHC class I antigen presentation by HCMV; lessons for tumor immunology

MHC class I antigen presentation is a tightly regulated process that begins in the cell cytoplasm with the generation of peptide ligands by the proteasome (1, 2). Peptides are translocated from the cytosol into the endoplasmic reticulum (ER) lumen through the MHC-encoded TAP complex. These peptides are loaded onto the class I heterodimer that is comprised of a 43 kDa type I membrane glycoprotein heavy chain and a 12 kDa soluble light chain (p2m). Shortly after synthesis of the class I heavy chain and &m, the complex is properly folded with assistance from ER resident chaperones such as calnexin, calreticulin and the thiol-reductase, ERp57(3). Tapasin, an ER-resident protein that associates with TAP, can interact with peptide-free class I heterodimerkhaperone complex and guide it to the TAP, where it is subsequently loaded with peptide. The generation of the trimeric class I complex allows its exit out of the ER and through the Golgi to the cell surface. The major histocompatibility complex (MHC) class I molecules present peptides derived from microbial and cellular proteins on the cell surface (4). The interaction of the MHC class I molecules with cytotoxic CD8'T lymphocytes (CTL) can activate an immune response and target the host cell for lysis, thereby eliminating the infected or abnormal cell. Several viruses and tumor cells can down-regulate the surface expression of class I molecuies at the transcriptional and post-translational levels(5, 6). The prevention of class I surface expression allows these cells to escape CTL detection. The mechanism by which tumors down-regulate class I molecules is not clearly understood. However, viral proteins have been identified which interfere with class I antigen presentation and may provide insight into how class I down-regulation is achieved in tumor cells as well.