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Articles

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.

Key Words: tumor • natural killer cell • recruitment • tumor necrosis factor • perforin

M.J. Smyth is currently supported by Wellcome Trust Australasian Senior Research Fellowship and by Project Grants from the National Health and Medical Research Council of Australia. J.D. Sedgwick and H. Körner were supported by a Program Grant from the National Health and Medical Research Council of Australia and Project Grants from the Multiple Sclerosis Society of Australia.

Dr. Korner's current address is the Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Wasserturmstrasse 3, D-91054 Erlangen, Germany. Dr. Sedgwick's current address is DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, CA 94304-1104.

Abbreviations used: B6, C57BL/6; CNS, central nervous system; EAE, experimental allergic encephalomyelitis; FasL, Fas ligand; LU₂₅, the number of effector cells required to lyse 25% of the target cells; P⁰, perforin-deficient; poly-IC, polyinosinic-polycytidylic acid; TNF⁰, TNF-deficient; VCAM-1, vascular adhesion molecule 1.

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