Activating Ly-49D and inhibitory Ly-49A natural killer cell receptors demonstrate distinct requirements for interaction with H2-D(d).
The activating Ly-49D receptor and the inhibitory Ly-49A receptor mediate opposing effects on natural killer (NK) cell cytotoxicity after interaction with the same major histocompatibility complex ligand, H2-D(d). To compare Ly-49D and Ly-49A interactions with H2-D(d), we created mutations in H2-D(d) and examined the functional ability of these mutants to activate lysis through Ly-49D or to inhibit lysis through Ly-49A. Specific single amino acid changes in either the H2-D(d) alpha(1) helix or the alpha(2) helix abrogated Ly-49D-mediated cytotoxicity, but these changes had no significant effect on Ly-49A-dependent inhibition. Each of three alpha(2) domain mutations in the floor of the peptide binding groove reduced functional recognition by either Ly-49D or Ly-49A, but all three were required to fully abrogate inhibition by Ly-49A. Our studies indicate that Ly-49D/H2-D(d) interactions require distinct determinants compared with Ly-49A/H2-D(d) interactions. These differences have important implications for the integration of activating and inhibitory signals in NK cells.
Department of Medicine, University of California, San Francisco, California 94143, USA. marynak@itsa.ucsf.edu
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Nakamura
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Hayashi
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Niemi
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Ryan
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Seaman
D019943:Amino Acid Substitution; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D016296:Mutagenesis; D010455:Peptides / Q000276:immunology; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000276:immunology*; D055630:Receptors, NK Cell Lectin-Like
D000950:Antigens, Ly; D002352:Carrier Proteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010455:Peptides; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like