The human neuroblastoma cell line T98G is sensitive to the antiproliferative activity of both alpha- and gamma-interferons (IFNs). Specific binding of a homogeneous 125I-IFN-alpha 2 probe to high-affinity membrane receptors (apparent Kd = 6.2 X 10(-10) M) can be decreased by pretreatment of these cells with human IFN-gamma (HuIFN-gamma, derived by recombinant DNA techniques). The regulation of HuIFN-alpha 2 binding by such pretreatment is reflected by subsequent inhibition of both the antiviral and antiproliferative activities of HuIFN-alpha 2 on T98G cells. Thus, binding of HuIFN-gamma to its distinct cell-surface receptor can modify expression of the separate IFN-alpha receptor, presumably through an indirect effect on the apparent Kd of the IFN-alpha 2 receptor-ligand interaction.