IL-12 receptor β2 (IL-12Rβ2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites

Two subunits of the IL-12 receptor (IL-12R), IL-12R beta1 and IL-12R beta2, have been identified and cloned. Previous studied dem demonstrated that the IL-12R beta1 subunit was required for mouse T and NK cells to respond to IL-12 in vivo. To investigate the role of IL-12R beta2 in IL-12 signaling, we have generated IL-12R beta2-deficient (IL-12R beta2(-/-)) mice by targeted mutation in embryonic stem (ES) cells, Although Con A-activated splenocytes from IL-12R beta2(-/-) mice still bind IL-12 with both high and low affinity, no IL-12-induced biological functions can be detected, Con A-activated splenocytes of IL-12R beta2(-/-) mice failed to produce IFN-gamma or proliferate in response to IL-12 stimulation. NK lytic activity of IL-12R beta2(-/-) splenocytes was not induced when incubated with IL-12, IL-12R beta2(-/-) splenocytes were deficient in IFN-gamma secretion when stimulated with either Con A or anti-CD3 mAb in vitro, Furthermore, IL-12R beta2(-/-) mice were deficient in vivo in their ability to produce IFN-gamma following endotoxin administration and to generate a type I cytokine response, IL-12-mediated signal transduction was also defective as measured by phosphorylation of STAT4, These results demonstrate that although mouse IL-12R beta1 is the subunit primarily responsible for binding IL-12, IL-12R beta2 plays an essential role in mediating the biological functions of IL-12 in mice.