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 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.
Lai
S Y
SY
Gladstone Institute of Virology and Immunology, San Francisco, California 94141-9100, USA.
Molden
J
J
Goldsmith
M A
MA
D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects; D016764:Cell Polarity; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D008040:Genetic Linkage; D006801:Humans; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism*; D020395:Receptors, Interleukin-7; D016511:Severe Combined Immunodeficiency / Q000209:etiology* / Q000235:genetics*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics*
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases