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 struc turally diverse receptors that inhibit target cell lysis upon recognit ion of major histocompatibility complex (MHC) class I molecules expres sed 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 speci ficity in NK inhibition mediated by Ly-49A in the mouse, human histoco mpatibility antigen (HLA)-B2705-specific NK clones displayed selectiv ity for peptides. In this report, we examine the role of peptide in th e recognition of HLA-C by the defined killer cell inhibitory receptor (KIR) c142 with established specificity for HLA-Cw4. Binding of solubl e KIR c142 molecules to HLA-Cw4 expressed on transporter associated wi th 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 peptid e QYDDAVYKL abolished Cw4 interaction with KIR c142 despite similar su rface expression of HLA-C. The specificity of this direct interaction between peptide-loaded HLA-Cw4 on RMA-S cells and soluble KIR c142 cor related with recognition by NK clones in that they were inhibited only by HLA-Cw4 loaded with the appropriate peptides.