Expression of IFN-gamma upon triggering of activating Ly49D NK receptors in vitro and in vivo: costimulation with IL-12 or IL-18 overrides inhibitory receptors.
NK cells can express both activating and inhibitory Ly49 receptors on their cell surface. When cells expressing both receptors are presented with a ligand, inhibition dominates the functional outcome. In this report we demonstrate that costimulation of the activating Ly49D murine NK cell receptor with IL-12 or IL-18 is capable of over-riding the inhibitory Ly49G2 receptor blockade for cytokine production both in vitro and in vivo. This synergy is mediated by and dependent upon Ly49D-expressing NK cells and results in significant systemic expression of IFN-gamma. This would place NK cells and their activating Ly-49 receptors as important initiators of microbial, antiviral, and antitumor immunity and provide a mechanism for the release of activating Ly49 receptors from inhibitory receptor blockade.
Ortaldo
John R
JR
Laboratory of Experimental Immunology, National Cancer Institute-Center for Cancer Research, B-560, Room 31-93, Frederick, MD 21702-1201, USA. ortaldo@mail.ncifcrf. gov
Young
Howard A
HA
D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004357:Drug Synergism; D007272:Injections, Intralymphatic; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology*; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D055650:NK Cell Lectin-Like Receptor Subfamily A; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D055630:Receptors, NK Cell Lectin-Like; D014407:Tumor Cells, Cultured
D000950:Antigens, Ly; D003432:Cross-Linking Reagents; D016207:Cytokines; D020382:Interleukin-18; C527092:Klra4 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D055650:NK Cell Lectin-Like Receptor Subfamily A; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D018664:Interleukin-12; D007371:Interferon-gamma