REDUCED CELL-SURFACE EXPRESSION OF HLA-C MOLECULES CORRELATES WITH RESTRICTED PEPTIDE BINDING AND STABLE TAP INTERACTION

HLA-C molecules are poorly expressed at the cell surface compared with HLA-A and HLA-B locus products, The reason for the low surface expres sion and the underlying mechanism is unclear, We show that the HLA-C4 allele is expressed intracellularly in amounts similar to HLA-A and HL A-B alleles. However, the majority of the HLA-C4 molecules is not tran sported, but is retained in the endoplasmic reticulum by stable intera ction with TAP, This pool does not appear to participate in the format ion of HLA-C4/peptide complexes, but is degraded in the endoplasmic re ticulum. HLA-C4 molecules can dissociate from TAP upon binding of spec ific peptide, However, they require a 10-fold higher concentration of a completely degenerated 9-mer peptide mixture for release from TAP th an the HLA-A and HLA-B alleles, Our data show that the HLA-C molecules tested are more selective in their peptide binding than HLA-A and HLA -B molecules, resulting in prolonged association with TAP and a reduce d formation of intracellular HLA-C/peptide complexes. The restricted p eptide binding of certain HLA-C alleles provides one explanation for t he reduced expression of HLA-C molecules at the cell surface. Other me chanisms will be discussed.