title: An essential role for tumor necrosis factor in natural killer cell-mediated tumor rejection in the peritoneum.
abstract: Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I- variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I- RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3(-) NK1.1(+) cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I- prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte-mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I- tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.
authors.affiliation: Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria 3084, Australia. m.smyth@ari.unimelb.edu.au
authors.forename: M J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: J M
authors.initials: JM
authors.lastname: Kelly
authors.forename: A G
authors.initials: AG
authors.lastname: Baxter
authors.forename: H
authors.initials: H
authors.lastname: Körner
authors.forename: J D
authors.initials: JD
authors.lastname: Sedgwick
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology*; D054353:Perforin; D010537:Peritoneum / Q000276:immunology*; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin