Functional interactions between interleukin-4, interleukin-2, and tumor necrosis factor-alpha for lymphokine-activated killer cell generation.

The purpose of the present study was to explore the interaction between interleukin-2 (IL-2), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF) on the differentiation of human large granular lymphocytes (LGL) into lymphokine-activated killer cells (LAK). The data show that recombinant human IL-4 (100-1,000/ml) was able to induce the differentiation of human LGL into LAK effectors. The levels of the IL-4-induced cytotoxicity are significantly lower than those observed after stimulation of LGL by optimal doses of IL-2. This LAK activity generation by IL-4 was not associated with LGL proliferation. When TNF was added in LGL culture in the presence of suboptimal concentrations of IL-4, the lytic capacity of the activated killer cells was significantly enhanced, suggesting an apparent synergy between these two factors. Most interestingly, our data indicate that exogenous TNF can partially overcome the known inhibitory effect of IL-4 on IL-2-induced LGL differentiation into LAK effectors. These findings suggest a role for TNF in the process of LAK induction.