Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.
NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFNgamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.
Coudert
Jérôme D
JD
Ludwig Institute for Cancer Research, Lausanne Branch, Ch. des Boveresses 155, 1066 Epalinges, Switzerland.
Zimmer
Jacques
J
Tomasello
Elena
E
Cebecauer
Marek
M
Colonna
Marco
M
Vivier
Eric
E
Held
Werner
W
D000818:Animals; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000187:drug effects / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology*
D015815:Cell Adhesion Molecules; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma