Perforin, Fas Ligand, and Tumor Necrosis Factor Are the Major Cytotoxic Molecules Used by Lymphokine-Activated Killer Cells

Richard K Lee, Julie Spielman, Dong Yan Zhao, Kristin J. Olsen, Eckhard R. Podack

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Abstract

Lymphokine-activated killer (LAK) cells generated from perforin knockout mice possess significantly reduced cytotoxicity against a panel of tumor target cell lines, with some tumor cells being lysed exclusively by the perforin pathway. LAK cells are also capable of Fas ligand-mediated cytotoxicity. LAK cells generated from mice deficient in both perforin and Fas ligand (PKO/gld) were not cytolytic in short term cytotoxicity assays, demonstrating that perforin and Fas ligand are required for acute target cell lysis. However, PKO/gld LAK cells were cytotoxic in long term cytotoxicity assays against TNF-sensitive tumor lines, and this cytotoxicity was completely inhibited by neutralizing TNF Abs. This potent TNF cytotoxicity has not been fully appreciated previously because of the presence of dominant-acting perforin and Fas ligand in acute tumor cell lysis. TNF-based cytotoxicity by PKO/gld LAK was both soluble and membrane bound, and both forms of TNF were constitutively expressed. Thus, LAK cells are armed with at least three cytotoxic molecules: perforin, Fas ligand, and TNF.

Original languageEnglish
Pages (from-to)1919-1925
Number of pages7
JournalJournal of Immunology
Volume157
Issue number5
StatePublished - Sep 1 1996

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Lymphokine-Activated Killer Cells
Perforin
Fas Ligand Protein
Tumor Necrosis Factor-alpha
Neoplasms
Lymphokines
Tumor Cell Line
Knockout Mice
Membranes

ASJC Scopus subject areas

  • Immunology

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Perforin, Fas Ligand, and Tumor Necrosis Factor Are the Major Cytotoxic Molecules Used by Lymphokine-Activated Killer Cells. / Lee, Richard K; Spielman, Julie; Zhao, Dong Yan; Olsen, Kristin J.; Podack, Eckhard R.

In: Journal of Immunology, Vol. 157, No. 5, 01.09.1996, p. 1919-1925.

Research output: Contribution to journalArticle

Lee, Richard K ; Spielman, Julie ; Zhao, Dong Yan ; Olsen, Kristin J. ; Podack, Eckhard R. / Perforin, Fas Ligand, and Tumor Necrosis Factor Are the Major Cytotoxic Molecules Used by Lymphokine-Activated Killer Cells. In: Journal of Immunology. 1996 ; Vol. 157, No. 5. pp. 1919-1925.
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AB - Lymphokine-activated killer (LAK) cells generated from perforin knockout mice possess significantly reduced cytotoxicity against a panel of tumor target cell lines, with some tumor cells being lysed exclusively by the perforin pathway. LAK cells are also capable of Fas ligand-mediated cytotoxicity. LAK cells generated from mice deficient in both perforin and Fas ligand (PKO/gld) were not cytolytic in short term cytotoxicity assays, demonstrating that perforin and Fas ligand are required for acute target cell lysis. However, PKO/gld LAK cells were cytotoxic in long term cytotoxicity assays against TNF-sensitive tumor lines, and this cytotoxicity was completely inhibited by neutralizing TNF Abs. This potent TNF cytotoxicity has not been fully appreciated previously because of the presence of dominant-acting perforin and Fas ligand in acute tumor cell lysis. TNF-based cytotoxicity by PKO/gld LAK was both soluble and membrane bound, and both forms of TNF were constitutively expressed. Thus, LAK cells are armed with at least three cytotoxic molecules: perforin, Fas ligand, and TNF.

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