Immunodeficiency due to defective antigen processing: the molecular basis for type 1 bare lymphocyte syndrome.

(MHC) class I molecules are polymorphic cell surface glycoproteins that play an essential role in immune surveillance. In the MHC class I antigen presentation pathway, peptides derived from cytosolic proteasome-mediated proteolysis are transported into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP), reviewed in ref. 1. In the ER lumen, translocated peptides bind to newly synthesized complexes of MHC class I heavy chains and β2-microglobulin (β2m). Binding is facilitated by the transient association of class I heterodimers and TAP, an interaction that is bridged by the ER-resident protein tapasin (Fig. 1 and ref. 2). Peptide binding to MHC class I molecules is believed to result in structural changes that lead to the dissociation of peptideMHC complexes from TAP complexes and tapasin, and their subsequent transit to the cell surface, reviewed in ref. 1. Cell surface display of foreign peptides in complex with MHC class I molecules allows for CD8+ αβ T cell–mediated recognition of cells that bear intracellular pathogens. TAP comprises two structurally related subunits, which interact to form a functional peptide-transporting complex (Fig. 1). Prior to peptide translocation by TAP, peptides bind to the membrane-proximal, cytosolic surface of TAP1/TAP2 complexes (3). Hydrolysis of ATP results in peptide translocation into the ER lumen, reviewed in ref. 1. Studies with mutant mammalian cell lines have shown that both TAP1 and TAP2 are required for peptide binding to TAP (3), as well as for peptide translocation into the ER (4). Defects in either protein result in an impairment in peptide translocation, and in the absence of class I–specific peptides in the ER. MHC class I molecules that are not complexed with peptides are unstable, inefficiently transported through the Golgi, and poorly expressed at the cell surface, reviewed in ref. 5. Cells derived from mutant mice with a disrupted TAP1 gene show highly reduced levels of surface MHC class I molecules, and are also