J. Exp. Med., Volume 188, Number 9, November 2, 1998 1611-1619

An Essential Role for Tumor Necrosis Factor in Natural Killer Cell-mediated Tumor Rejection in the Peritoneum

By Mark J. Smyth,^* Janice M. Kelly,^* Alan G. Baxter, Heinrich Körner, and Jonathon D. Sedgwick

From the ^* Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria 3084, Australia; and the  Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia

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.

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