MHC class l/β2-microglobulin complexes associate with TAP transporters before peptide binding

MAJOR histocompatibility complex class I molecules bind antigenic peptides in the endoplasmic reticulum (ER) and transport them to the cell surface for recognition by cytotoxic T lymphocytes. The peptides are predominantly generated from cytoplasmic proteins, probably by the action of the multicatalytic proteinase complex, or proteasome 1,2 . They are transported into the ER by the transporters associated with antigen processing (TAP), a complex formed from two subunits, TAP.l and TAP.2 (refs 3–5). Here we show that the TAP molecules are intimately involved in the assembly of the class I/β 2 -microglobulin (β 2 m) peptide complex. Free class I heavy chains are associated in the ER with the chaperone calnexin 6,7 . In human B-cell lines, however, class I/β 2 m dimers in the ER are physically associated with TAP molecules rather than calnexin. Our results suggest that calnexin mediates class I/β 2 m dimerization, and subsequent binding of the dimers to TAP molecules facilitates their association with TAP-transported peptides.