The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity.

Natural killer (NK) cells in mice and humans express a number of structurally diverse receptors that inhibit target cell lysis upon recognition of major histocompatibility complex (MHC) class I molecules expressed on targets. The contribution of peptide to the structural features of class I required for NK cell inhibition appears to vary depending on the type of receptor engaged. Thus, while there is no peptide specificity in NK inhibition mediated by Ly-49A in the mouse, human histocompatibility antigen (HLA)-B*2705-specific NK clones displayed selectivity for peptides. In this report, we examine the role of peptide in the recognition of HLA-C by the defined killer cell inhibitory receptor (KIR) cl42 with established specificity for HLA-Cw4. Binding of soluble KIR cl42 molecules to HLA-Cw4 expressed on transporter associated with antigen presentation (TAP)-deficient RMA-S cells occurred only upon exogenous peptide loading. Moreover, there was peptide selectivity in that certain substitutions at positions 7 and 8 of the nonamer peptide QYDDAVYKL abolished Cw4 interaction with KIR cl42 despite similar surface expression of HLA-C. The specificity of this direct interaction between peptide-loaded HLA-Cw4 on RMA-S cells and soluble KIR cl42 correlated with recognition by NK clones in that they were inhibited only by HLA-Cw4 loaded with the appropriate peptides.