Interleukin‐4 differentially regulates interleukin‐2‐mediated and CD2‐mediated induction of human lymphokine‐activated killer effectors

Natural killer (NK) cells can be differentiated into lymphokine‐activated killer (LAK) effectors following stimulation with interleukin (IL)‐2. This induction can be negatively regulated by IL‐4. In this study, we demonstrate that the stimulation of NK cells through the CD2 pathway with (9‐1 + 9.6) monoclonal antibodies can also induce these cells to secrete tumor necrosis factor‐α (TNF‐α) and to differentiate into LAK effectors. More importantly, our data indicate that, in contrast to the IL‐2‐induced LAK generation, the anti‐CD2‐triggered LAK activity was not regulated by IL‐4. IL‐4 was found to enhance the LAK activity as well as NK cell proliferation following activation with anti‐CD2 by a mechanism involving, at least in part, an increased TNF‐α production. Using immobilized monoclonal antibodies against the Fc receptor (FcγRIII or CD16) for NK stimulation, we also observed that the anti‐CD16‐induced LAK activity was not inhibited by IL‐4. These data further point to a pivotal role of TNF‐α as a regulatory cytokine in anti‐CD2‐induced LAK generation, and suggest that IL‐4 could serve as a discriminatory factor between two distinct pathways involved in the activation of non‐MHC‐restricted cytotoxicity.