SHARED GAMMA(C) SUBUNIT WITHIN THE HUMAN INTERLEUKIN-7 RECEPTOR COMPLEX - A MOLECULAR-BASIS FOR THE PATHOGENESIS OF X-LINKED SEVERE COMBINED IMMUNODEFICIENCY

Genetic evidence suggests that mutations in the gamma(c) receptor subu nit cause X-linked severe combined immunodeficiency (X-SCID). The gamm a(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 th e severe phenotype of X-SCID patients. Interestingly, gene disruption of either IL-7 or the IL-7 receptor (IL-7R) alpha subunit in mice lead s to immunological defects that are similar to human X-SCID. These obs ervations suggest the functional importance of gamma(c) in the IL-7R c omplex. In the present study, structure/function analyses of the IL-7R complex using a chimeric receptor system demonstrated that gamma(c) i s indeed critical for IL-7R function. Nonetheless, only a limited port ion of the cytoplasmic domain of gamma(c) is necessary for IL-7R signa l transduction. Furthermore, replacement of the gamma(c) cytoplasmic d omain by a severely truncated erythropoeitin receptor does not affect measured IL-7R signaling events. These findings support a model in whi ch gamma(c) serves primarily to activate signal transduction by the IL -7R complex, while IL-7R alpha determines specific signaling events th rough its association with cytoplasmic signaling molecules. Finally, t hese studies are consistent with the hypothesis that the molecular pat hogenesis of X-SCID is due primarily to gamma(c)-mediated defects in t he IL-7/IL-7R system.