Ly-49-independent inhibition of natural killer cell-mediated cytotoxicity by a soluble major histocompatibility complex class I molecule

Natural killer (NK) cells lyse their targets in a non-major histocompatibility complex (MHC)-restricted manner, and the cytotoxicity can be inhibited by a number of MHC class I allele products, suggesting that NK cells may have a “positive receptor” that recognizes the target and a “negative receptort” that receives an inhibitory signal from class I. Since negative receptors could also exert their effect by masking a positive ligand, we have determined whether there may be a direct interaction between class I and an NK surface receptor by measuring cytotoxicity in the presence of a soluble class I molecule, K^d. Soluble K^d at micromolar concentrations could efficiently block NK cell cytotoxicity, suggesting that class I has a direct effect on cytotoxicity, rather than masking another target cell ligand. Inhibition required that K^d be at least divalent, probably because of its higher affinity or its ability to cross-link the NK surface receptor. In addition, the effect was independent of the peptide used to load K^d, and there was inhibition of cytotoxicity of NK cells derived from either H-2^d or H-2^b mice. Finally, depletion of NK cells expressing Ly-49 had no effect on the specific inhibition by K^d, raising the possibility that NK cells are endowed with additional negative receptors besides Ly-49. Taken together, these results suggest that there may be a family of NK receptors recognizing different class I alleles, which can receive negative signals by directly binding to class I on the target cell surface.