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Reduced Cell Surface Expression of HLA-C Molecules Correlates with Restricted Peptide Binding and Stable TAP Interaction¹

Anne Neisig^*, Cornelis J. M. Melief and Jacques Neefjes^2,*

^* Department of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; and Department of Immunohematology and Blood Bank, University Hospital Leiden, Leiden, The Netherlands

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 expression and the underlying mechanism is unclear. We show that the HLA-C4 allele is expressed intracellularly in amounts similar to HLA-A and HLA-B alleles. However, the majority of the HLA-C4 molecules is not transported, but is retained in the endoplasmic reticulum by stable interaction with TAP. This pool does not appear to participate in the formation of HLA-C4/peptide complexes, but is degraded in the endoplasmic reticulum. HLA-C4 molecules can dissociate from TAP upon binding of specific peptide. However, they require a 10-fold higher concentration of a completely degenerated 9-mer peptide mixture for release from TAP than 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 reduced formation of intracellular HLA-C/peptide complexes. The restricted peptide binding of certain HLA-C alleles provides one explanation for the reduced expression of HLA-C molecules at the cell surface. Other mechanisms will be discussed.

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