SYNERGY OF TUMOR NECROSIS FACTOR AND INTERLEUKIN-2 IN THE ACTIVATION OF HUMAN CYTO-TOXIC LYMPHOCYTES - EFFECT OF TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-2 IN THE GENERATION OF HUMAN LYMPHOKINE-ACTIVATED KILLER CELL CYTO-TOXICITY

Abstract

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.