Genetic evidence suggests that mutations in the gamma(c) receptor subunit cause X-linked severe combined immunodeficiency (X-SCID). The gamma(c) subunit can be employed in receptor complexes for IL-2, -4, -7, -9, and -15, and the multiple signaling defects that would result from a defective gamma(c) chain in these receptors are proposed to cause the severe phenotype of X-SCID patients. Interestingly, gene disruption of either IL-7 or the IL-7 receptor (IL-7R) alpha subunit in mice leads to immunological defects that are similar to human X-SCID. These observations suggest the functional importance of gamma(c) in the IL-7R complex. In the present study, structure/function analyses of the IL-7R complex using a chimeric receptor system demonstrated that gamma(c) is indeed critical for IL-7R function. Nonetheless, only a limited portion of the cytoplasmic domain of gamma(c) is necessary for IL-7R signal transduction. Furthermore, replacement of the gamma(c) cytoplasmic domain by a severely truncated erythropoeitin receptor does not affect measured IL-7R signaling events. These findings support a model in which gamma(c) serves primarily to activate signal transduction by the IL-7R complex, while IL-7R alpha determines specific signaling events through its association with cytoplasmic signaling molecules. Finally, these studies are consistent with the hypothesis that the molecular pathogenesis of X-SCID is due primarily to gamma(c)-mediated defects in the IL-7/IL-7R system.