Differential inhibition of lymphokine-activated killing, proliferation, and cytokine secretion by humanized antibodies against the low- and intermediate-affinity interleukin-2 receptors: A novel model for activation of human peripheral blood mononuclear cells by interleukin 2

Human PBMCs generate LAK, proliferate, and secrete secondary cytokines in response to IL-2. We assessed the roles of the various receptor complexes in these responses to IL-2 using antibodies that block the interaction of IL-2 with the intermediate-affinity IL-2R (humanized Mikβ1) and high- and low-affinity interactions (HTac). The HTac antibody produced dramatic reductions in proliferation (27%) and in the secretion of cytokines (TNF)-α and -β and IFN-γ inhibited 68%, 72%, and 80%, respectively) with no decrease in LAK. HMik inhibited LAK activation by 65% and proliferation by 60% but had little effect on cytokine secretion. The combination of the two antibodies completely inhibited all proliferative, cytolytic, and secretory activity. These data suggest a novel model for the activation of human PBMCs by IL-2. Whereas induction of LAK activity is mediated through the intermediate-affinity IL-2R and cytokine secretion is mediated through the high-affinity complex, interaction between IL-2 and both of these receptor complexes is required for the induction and maintenance of proliferative activities in human PBMCs.