Excess β₂ microglobulin promoting functional peptide association with purified soluble class I MHC molecules

Abstract

T LYMPHOCYTES expressing αβ receptors recognize antigenic peptide fragments bound to major histocompatibility complex class I (ref. 1) or class II (ref. 2) molecules present on the surface membranes of other cells. Peptide fragments are present in the two available HLA crystal structures^3,4 and recent data indicate that peptide is required for the stable folding of the class I heavy chain and maintenance of its association with the class I light chain, β₂-microglobulin (β2m), at physiological temperature^5–7. To explain how the exogeneous peptide used to create targets for cytotoxic cells bearing CDS antigen¹ could associate with apparently peptide-filled extracellular class I molecules, we hypothesized that stable binding of exogenous peptide to mature class I molecules reflects either the replacement of previously bound peptide during the well documented β2m exchange process8 or the loading of 'empty' class I heavy chains dependent on the availability of excess β 2m. In either case, free β2m should enhance peptide/class I binding. Using either isolated soluble class I molecules or living cells, we show here that free purified β2m markedly augments the generation of antigenic complexes capable of T-cell stimulation.