The functional high-affinity IL-12 receptor is composed of at least two ♀-type receptor subunits, each independently exhibiting a low affinity for IL-12. Both subunits are members of the cytokine receptor superfamily. IL-12 p40 interacts primarily with IL-12 R♀1, while IL-12 p35 interacts primarily with the signal-transducing ♀2 subunit. IL-12 signaling involves activation of the receptor-associated tyrosine kinases JAK2 and TYK2 and downstream tyrosine phosphorylation of the transcription factors STAT3 and STAT4 (the central signal transducer of IL-12). The IL-12R is expressed primarily on activated T andNK cells. Expression of the ♀2 subunit determines TH1 development since the ♀2 component is selectively downregulated on TH2 cells. Inhibiting IL-12 responsiveness represents an experimental therapy for TH1-driven inflammatory and autoimmune diseases.