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 receptor" 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, Kd. Soluble Kd 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 Kd 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 Kd, and there was inhibition of cytotoxicity of NK cells derived from either H-2d or H-2b mice. Finally, depletion of NK cells expressing Ly-49 had no effect on the specific inhibition by Kd, 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.
Roth
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Institut Pasteur, Unité de Biologie Moléculaire du Gène, INSERM U277, Paris, France.
Kourilsky
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Ojcius
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DM
D000818:Animals; D000950:Antigens, Ly; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011971:Receptors, Immunologic / Q000276:immunology*; D055630:Receptors, NK Cell Lectin-Like
D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like