An essential role for tumor necrosis factor in natural killer cell-mediated tumor rejection in the peritoneum

• Published in: The Journal of experimental medicine Vol. 188; no. 9; pp. 1611 - 1619
• Main Authors: Smyth, M J, Kelly, J M, Baxter, A G, Körner, H, Sedgwick, J D
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 02.11.1998
• Subjects: Animals; Cell Movement - immunology; Cytotoxicity, Immunologic; Graft Rejection - immunology; Histocompatibility Antigens Class I - metabolism; In Vitro Techniques; Killer Cells, Natural - immunology; Killer Cells, Natural - physiology; Male; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neoplasm Transplantation; Neoplasms, Experimental - immunology; Perforin; Peritoneum - immunology; Pore Forming Cytotoxic Proteins; Tumor Necrosis Factor-alpha - deficiency; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.188.9.1611

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.