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Synergy of Tumor Necrosis Factor and Interleukin 2 in the Activation of Human Cytotoxic Lymphocytes: Effect of Tumor Necrosis Factor and Interleukin 2 in the Generation of Human Lymphokine-activated Killer Cell Cytotoxicity

Departments of Tumor Biology [L. B. O-S., E. A. G.], Clinical Immunology [J. U. G.], and Surgery [E. A. G.], M. D. Anderson Hospital, The University of Texas System Cancer Center, Houston, Texas 77030

Human lymphocytes can respond to interleukin 2 (IL-2) under serumfree conditions with generation of major histocompatibility locus-unrestricted oncolytic activity. This function has been named lymphokine activated killing (LAK). Although IL-2 is sufficient for the development of LAK, this function can be regulated positively by the addition of tumor necrosis factor or ß (TNF- or -ß). The cytotoxic synergy observed with TNF enables production of optimal LAK function at a 10-fold lower IL-2 concentration. Neither TNF- nor -ß is able to induce LAK function in the absence of IL-2. Using TNF- as a model, we demonstrate that (a) the cytotoxic synergy occurs with both fresh human tumors and cell lines; (b) the degree of IL-2/TNF- synergy, for most peripheral blood lymphocyte donors, is dependent upon the IL-2 concentration used for activation with the most striking synergy observed at lower IL-2 doses; (c) synergy is specific for TNF- and can be abrogated by neutralizing antibody against this cytokine; (d) addition of high-dose neutralizing antibody to IL-2 alone-stimulated peripheral blood lymphocytes can reduce the cytotoxicity capacity of these effectors suggesting an immunoregulatory role for endogenous TNF-; and (e) TNF- addition to IL-2-stimulated peripheral blood lymphocytes does not increase proliferation or cell recovery but does result in enhanced IL-2 receptor expression. Collectively, our results suggest that TNF- (and -ß) have immunopotentiating roles in the amplification of non-major histocompatibility locus-restricted lymphocyte effector function.

¹ To whom requests for reprints should be addressed, at Department of Tumor Biology, Box 79, M. D. Anderson Hospital and Tumor Institute, University of Texas System Cancer Center, Houston, TX 77030.

Received 8/31/87. Revised 11/13/87. Accepted 11/17/87.