Shared gamma(c) subunit within the human interleukin-7 receptor complex - A molecular basis for the pathogenesis of X-linked severe combined immunodeficiency
Shared gamma(c) subunit within the human interleukin-7 receptor complex - A molecular basis for the pathogenesis of X-linked severe combined immunodeficiency
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DOI：
10.1172/jci119144
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发表时间：
1997-01-15
影响因子：
15.9
通讯作者：
Goldsmith, MA
中科院分区：
文献类型：
--
作者：
Lai, SY;Molden, J;Goldsmith, MA
遗传学证据表明，γ（c）受体亚单位的突变导致X连锁严重联合免疫缺陷（X-SCID）。γ（c）亚基可用于IL-2、IL-4、IL-7、IL-9和IL-15的受体复合物中，并且这些受体中缺陷的γ（c）链导致的多重信号传导缺陷被认为是导致X-SCID患者的严重表型的原因。有趣的是，小鼠中IL-7或IL-7受体（IL-7 R）α亚基的基因破坏导致与人X-SCID相似的免疫缺陷。这些观察结果表明γ（c）在IL-7 R复合物中的功能重要性。在本研究中，使用嵌合受体系统对IL-7 R复合物进行结构/功能分析，证明γ（c）确实对IL-7 R功能至关重要。尽管如此，γ（c）的胞质结构域的仅有限部分对于IL-7 R信号转导是必需的。此外，γ（c）胞质结构域被严重截短的促红细胞生成素受体替代不影响测量的IL-7 R信号传导事件。这些发现支持了一个模型，其中γ（c）主要用于激活IL-7 R复合物的信号转导，而IL-7 R α通过其与细胞质信号分子的结合决定特定的信号转导事件。最后，这些研究与X-SCID的分子发病机制主要是由于IL-7/IL-7 R系统中γ（c）介导的缺陷的假设一致。
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.