Peptide dependency and selectivity of the NK cell inhibitory receptor Ly-49C

MHC class I molecules can prevent NK cell-mediated cytotoxicity by interact ing with inhibitory receptors on the effector cells. Different conclusions have been reached regarding possible peptide selectivity of these receptors . To address whether peptide selectivity is an exclusive feature of human o r immunoglobulin-superfamily receptors, we have studied a system based on t he murine NK receptor Ly-49C in the lectin-superfamily. Loading of TAP-defi cient RMA-S cells with the H-2K(b)-restricted, ovalbumin-derived peptide OV A(257-264) (pOVA) induced their ability to bind Ly-49C-transfected reporter cells, and also protected them from killing by Ly-49C(+) NK cells. Other p eptides that bound and stabilized H-2K(b) equally well differed in their NK protective capacity. Comparison of the MHC class I peptide complexes (crys tal structures and molecular models) revealed a conformational motif encomp assing the C-terminal parts of the alpha 1 helix (73-77) and the bound pept ide that was common for the protective complexes. Substitution analysis of pOVA suggested that position 7 in the peptide may be critical for optimal p rotection as well as for the conformational motif at position 73-77. In con clusion, protection mediated by the murine C-type lectin receptor Ly-49C is peptide dependent and selective.