The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand.
Natural killer (NK) cells are inhibited from killing cellular targets by major histocompatibility complex (MHC) class I molecules. In the mouse, this can be mediated by the Ly-49A NK cell receptor that specifically binds the H-2Dd MHC class I molecule, then inhibits NK cell activity. Previous experiments have indicated that Ly-49A recognizes the alpha 1/alpha 2 domains of MHC class I and that no specific MHC-bound peptide appeared to be involved. We demonstrate here that alanine-substituted peptides, having only the minimal anchor motifs, stabilized H-2Dd expression and provided resistance to H-2Dd-transfected, transporter associated with processing (TAP)-deficient cells from lysis by Ly-49A+ NK cells. Peptide-induced resistance was blocked only by an mAb that binds a conformational determinant on H-2Dd. Moreover, stabilization of "empty" H-2Dd heavy chains by exogenous beta 2-microglobulin did not confer resistance. In contrast to data for MHC class I-restricted T cells that are specific for peptides displayed MHC molecules, these data indicate that NK cells are specific for a peptide-induced conformational determinant, independent of specific peptide. This fundamental distinction between NK cells and T cells further implies that NK cells are sensitive only to global changes in MHC class I conformation or expression, rather than to specific pathogen-encoded peptides. This is consistent with the "missing self" hypothesis, which postulates that NK cells survey tissues for normal expression of MHC class I.
Orihuela
M
M
Department of Medicine and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Margulies
D H
DH
Yokoyama
W M
WM
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly; D001665:Binding Sites; D002460:Cell Line; D006183:H-2 Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000737:chemistry / Q000502:physiology; D055630:Receptors, NK Cell Lectin-Like; D013234:Stem Cells; D014162:Transfection; D001613:beta 2-Microglobulin / Q000276:immunology
D018528:ATP-Binding Cassette Transporters; D000950:Antigens, Ly; D006183:H-2 Antigens; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D001613:beta 2-Microglobulin