Functional interactions of IL2 and TNF in the differentiation of LGL into lak effectors

Abstract

We have previously reported on the synergistic effect of IL2 and TNF on the differentiation of LGL into LAK effectors. In the present study, we have further investigated the molecular basis of this synergistic mechanism and examined the role of TNF in the induction of LAK activity. We show that the generation of optimal LAK activity by low doses of IL‐2 in the presence of TNF involves the induction of high‐affinity IL2 receptors on LGL and occurs without promoting significant proliferation, suggesting a functional activation rather than a proliferative expansion of LAK precursors. Using blocking studies with anti‐Tac and with an anti‐IL2 (IHII), which specifically inhibits the binding of IL2 to the p75 IL2 receptor component, we also show that both the p55 and the p75 are involved in the increase in TNF binding sites on LGL and the subsequent acquisition of LAK activity. We also demonstrate that the failure of low doses of IL2 to induce LAK activity is related to their incapacity to induce TNF production. Moreover, when specific antibodies against TNF were added to the culture, the differentiation of LGL into LAK effectors by optimal concentrations of IL2 in our system (2.5–5.0 ng/ml) was partially inhibited. This suggests that TNF may be a physiologic mediator in the sequential activation stages of LGL into LAK effectors.