NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors.
Interaction of the activating ligand H60 with NKG2D receptor constitutes a major stimulatory pathway for natural killer (NK) cells. The influence of inhibitory Ly49 receptors on NKG2D-mediated activation is not clearly understood. Here we show that the magnitude of NKG2D-mediated cytotoxicity is directly proportional to both the levels of H60 and the nature of major histocompatibility complex (MHC) class I molecules expressed on the target cells. The expression levels of H60 on the target cells determined the extent to which the inhibition by Ly49C/I receptors can be overridden. In contrast, even a higher expression of H60 molecule on the target cells failed to overcome the inhibition mediated by Ly49A/G receptors. Also, the level of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generated by NK cells through anti-NKG2D monoclonal antibody (mAb)-mediated activation is significantly reduced by the presence of immobilized anti-Ly49A/G mAbs. Thus, NKG2D-mediated cytotoxicity and cytokine secretion results from the fine balance between activating and inhibitory receptors, thereby defining the NK cell-mediated immune responses.
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee 53226, USA.
Jeyarani
J
Regunathan
Yuhong
Y
Chen
Demin
D
Wang
Subramaniam
S
Malarkannan
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015536:Down-Regulation; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D008024:Ligands; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C527085:KLRK1 protein, human; C527088:Klra1 protein, mouse; C527091:Klra3 protein, mouse; C527086:Klrk1 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; C114735:minor H antigen H60