Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor alpha and interleukin 2 in the generation of human lymphokine-activated killer cell cytotoxicity.
Human lymphocytes can respond to interleukin 2 (IL-2) under serum-free 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 alpha or beta (TNF-alpha or -beta). The cytotoxic synergy observed with TNF enables production of optimal LAK function at a 10-fold lower IL-2 concentration. Neither TNF-alpha nor -beta is able to induce LAK function in the absence of IL-2. Using TNF-alpha 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-alpha 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-alpha 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-alpha; and (e) TNF-alpha 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-alpha (and -beta) have immunopotentiating roles in the amplification of non-major histocompatibility locus-restricted lymphocyte effector function.
Owen-Schaub
L B
LB
Department of Tumor Biology, M. D. Anderson Hospital, University of Texas System Cancer Center, Houston 77030.
Gutterman
J U
JU
Grimm
E A
EA
D002460:Cell Line; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha