The biological activities of IL-12 are mediated through a specific, high-affinity receptor composed of IL-12 receptor(R) β1 and IL-12Rβ2 subunits that exist primarily on T and NK cells. Remarkably, the expression of IL-12Rβ2 on CD4+ T cells in mouse and humans appears to be differentially regulated by IFN- γ and IFN-α, respectively. Using an antibody specific for the human IL-12Rβ2 subunit, the effect of IFN- γ, IFN- α, IL-12 and IL-2 on the regulation of IL-12R expression and IL-12 responsiveness of human T and NK cells was assessed. The presence of IFN- α or IFN- γ in cultures enhanced IL-12Rβ2 expression of CD4+ and CD8+ T cells. The enhancing effect of IFN- α and IFN- γ was independent of endogenous IL-12. Furthermore, the clearest effects of IFN- α and IFN- γ on IL-12Rβ2 expression on T cells were seen by abrograting the inhibition induced by the presence of IL-4 in cultures. In contrast to T cells, IFN-α and IFN-γ had little effect on regulating IL-12Rβ2 expression on human NK cells. Taken together, these data show that there is differential regulation of IL-12Rβ2 expression by IFN- α and IFN- γ on human T and NK cells.