title: NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1 expression on the tumor cells for optimal perforin-dependent effector function.
abstract: The NKG2D receptor on NK cells can recognize a variety of ligands on the tumor cell surface. Using a mouse renal cancer (Renca), we show that NKG2D recognition by NK cells was crucial for their ability to limit tumor metastases in vivo in both liver and lungs using perforin-dependent effector mechanisms. However, for the R331 cell line established from Renca, NKG2D recognition and perforin-dependent lysis played no role in controlling liver metastases. R331 cells were also more resistant to perforin-dependent lysis by NK cells in vitro. We therefore used these phenotypic differences between Renca and R331 to further investigate the crucial receptor:ligand interactions required for triggering lytic effector functions of NK cells. Reconstitution of R331 cells with ICAM-1, but not Rae-1gamma, restored NKG2D-mediated, perforin-dependent lysis. Interestingly, R331 cells were efficiently lysed by NK cells using death ligand-mediated apoptosis. This death ligand-mediated killing did not depend on NKG2D recognition of its ligands on tumor cells. This result suggests that the intracellular signaling in NK cells required for perforin and death ligand-mediated lysis of tumor target cell are quite distinct, and activation of both of these antitumor lytic effector functions of NK cells could improve therapeutic benefits for certain tumors.
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Building 560, Frederick, MD 21702, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Abdool
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brooks
authors.forename: Janice M
authors.initials: JM
authors.lastname: Kelly
authors.forename: Jeremy
authors.initials: J
authors.lastname: Swann
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
authors.forename: Earl W
authors.initials: EW
authors.lastname: Bere
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000502:physiology*; D055607:Receptors, Natural Killer Cell
chemical_list: C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C483886:perforin, mouse; D018799:Intercellular Adhesion Molecule-1