Binding of diverse peptides to MHC class I molecules inhibits target cell lysis by activated natural killer cells.

Class I MHC expression by target cells inhibits lysis mediated by natural killer (NK) cells, often in an allele-specific fashion. It has been proposed that NK cell inhibitory receptors recognize complexes of class I molecules with specific cellular peptides that define self, displacement of which would render cells NK sensitive. By loading the mostly empty Dd class I molecules of cell lines deficient in peptide transporter molecules with synthetic or natural Dd-bound peptides, we have demonstrated specific dose-dependent inhibition of the Ly49+ subset of activated NK cells by class I-peptide complexes. Inhibition occurred with most if not all Dd-binding peptides, suggesting that Ly49+ NK cells recognize class I-peptide complexes largely independently of peptide composition. The results suggest a primary role of NK cells in the destruction of cells that have down-regulated or extinguished cell surface expression of some or all class I molecules.