Tumor necrosis factor alpha: a costimulator for cytotoxic cell differentiation.

Large granular lymphocytes (LGL) can be activated by interleukin-2 (IL-2) into lymphokine-activated killers (LAK). Tumor Necrosis factor alpha was found to act synergistically with very low concentrations of IL-2 which were ineffective by themselves in inducing LAK activity. We demonstrate that the failure of low doses of IL-2 to induce LAK generation was related to their incapacity to induce TNF production by LGL. When specific antibodies against TNF were added to the culture, the differentiation of LGL into LAK effectors by optimal concentrations of IL-2 in our system was partially inhibited suggesting that TNF may be a physiologic mediator in the sequential activation stages of LGL into LAK effectors. We have also investigated the functional interaction between IL-2 and TNF on the generation of alloreactive CTL. Using primary mixed cultures of lymphocytes from a MHC-recombinant sibling identical for MHC class II antigens and displaying MHC class I disparity, our data indicate that addition of exogenous TNF at the sensitizing phase of the primary mixed lymphocyte reaction did not result in CTL activation. However, when simultaneously added with IL-2, TNF could promote an optimal induction of cytotoxic T cell generation. The TNF property to potentiate the cytotoxic function appears to involve an enhancement of IL-2 induced serine esterase activity suggesting that TNF may affect some components of the cellular lytic machinery. In conclusion the data presented here are most consistent with the suggestion that TNF could increase the IL-2 signaling efficiency or potentiate activation signaling involved in the acquisition of lytic competence by cytotoxic T cells.