Cytokine receptor γc chain mediated signal transduction and analysis of immunodeficiency by dysfunction of the γc chain

我们先前克隆的白细胞介素2受体γ链（IL-2Rγ）已知是人类x连锁严重联合免疫缺陷（X-SCID）的致病基因。X-SCID是一种发生率高达50%的原发性SCID患者的疾病，其特点是T、NK细胞严重缺陷，B细胞分化障碍。IL-2Rγ在几种细胞因子的受体中是共享的，被称为公共γ(γc)链。γ - c链的细胞质结构域与Jak3酪氨酸激酶相关，Jak3酪氨酸激酶的突变也会导致常染色体隐性SCID，即Jak3-SCID。这些观察结果表明，γc/Jak3信号通路对于T、NK和B细胞的发育是不可或缺的。因此，我们假设参与γc/Jak3信号通路的分子可能包括SCID的致病基因产物。在这种情况下，我们已经确定了与Jak3和Jak2相关的STAM1，并参与IL-2和GM-CSF介导的细胞增殖和c-myc诱导的信号传导。STAM1基因敲除小鼠出生发育正常，但5周龄后体重逐渐下降，低于正常小鼠的60-70%。90%的小鼠在16周龄前死亡。直到4周龄，STAM1基因敲除小鼠在临床上都是正常的，但在组织病理学上，它们在海马的CA3区表现出异常。另一方面，我们分子克隆了一个与STAM1同源的分子，命名为STAM2，发现STAM2在体外具有与STAM1相似的功能，提示STAM1敲除小鼠中STAM1可能被STAM2代偿。我们也培育了STAM2基因敲除小鼠，其生长正常，目前没有异常特征。我们现在正试图建立STAM1和STAM2的双KO小鼠，以研究它们可能的功能关系。

The interleukin 2 receptor γ chain (IL-2Rγ ), which we previously cloned, is known to be a causative gene for human X-linked severe combined immunodeficiency (X-SCID). X-SCID is a disease that occurs in as many as 50% of patients with primary SCID, and is characterized with profound defect of T and NK cells and impairment of B cell differentiation. The IL-2Rγ is shared among the receptors for several cytokines, and called the common γ(γc) chain. The cytoplasmic domain of the γc chain is associated with Jak3 tyrosine kinase, of which mutantions also cause an autosomal recessive SCID, Jak3-SCID. These observations suggest that the γc/Jak3 signaling pathway is indispensable for development of T, NK and B cells. We thus hypothesized that molecules involved in the γc/Jak3 signaling pathway may include causative gene products for SCID. In this context, we have identified STAM1, which is associated with Jak3 and Jak2, and involved in signaling for cell proliferation and c-myc induction mediated by IL-2 and GM-CSF. STAM1 knockout mice were born and developed normally, but their body weights decreased gradually after 5 weeks of age, and were below 60-70% of those of normal mice. 90% of the mice died before 16 weeks of age. Until 4 weeks of age, STAM1 knockout mice were normal clinically, but histopathologically they showed an abnormality in the CA3 region of the hippocampus. On the other hand, we molecularly cloned a STAM1 homologous molecule named STAM2, and revealed that STAM2 has similar in vitro functions to STAM1, suggesting that STAM1 may be compensated by STAM2 in the STAM1 knockout mice. We have also developed STAM2 knockout mice, which show normal growth and no abnormal features so far. We are now attempting to establish double KO mice for STAM1 and STAM2 to examine their possible functional relationship.