Cytokine receptor γc chain/Jak3 mediated signal transduction and analysis of immunodeficiecy by dysfunction of the γc chain/Jak3

我们鉴定并鉴定了白介素2受体γ链(IL-2Rγ)，该链的突变导致人类X连锁严重联合免疫缺陷病，该疾病发生在多达50%的原发联合免疫缺陷症患者中。研究发现，与γ链下游信号转导相关的JAK3基因突变也可引起常染色体隐性遗传性SCID。因此，我们考虑了JAK3下游可能存在与SCID相关的新基因，并首次发现了包括STAM在内的新的JAK3底物。在本研究中，利用基因打靶和转基因小鼠，我们分析了这些分子在体内的功能，以确定其参与γ链/JAK3的信号转导途径。(1)双缺陷小鼠，缺乏STAM1和STAM2，是胚胎致死的。为了进一步阐明STAM在淋巴细胞中的功能，我们建立了有条件地以淋巴细胞中同时缺乏这两种分子的小鼠为靶标。(2)HGS基因敲除(KO)小鼠对转化生长因子-β(转化生长因子-β)家族分子的刺激反应显著降低。(3)AMSH缺乏小鼠表现出出生后生长发育迟缓，并在第19天至23天之间死亡。表达Graf40突变体的转基因小鼠的胸腺细胞总数减少，而双阴性胸腺细胞亚群的胸腺细胞总数显著增加。

We identified and have characterized the interleukin 2 receptor γ chain (IL-2Rγ ), of which mutations cause Human X-linked severe combined immunodeficiency disease ( XSCID ), a disease that occurs in as many as 50 % of patients with primary SCID. It was found that mutations of Jak3, which is associated with and mediates the down stream signal transduction from the γ chain, also caused autosomal recessive SCID. Thus, we considered the possibility that there is the novel gene related to SCID down stream of Jak3 and then originally identified novel Jak3 substrates including STAM. In this study, using the gene targeting and transgenic mice we analyzed the in vivo function of the molecules to determine its involvement in the signal transduction pathway from γ chain /Jak3.( 1 ) Double deficient mice, lacking both STAM1 and STAM2, were embryonically lethal. To further elucidate the function of STAM in lymphocytes, we established conditionally targeting mice that will lack of both molecules in lymphocytes( 2 ) Hgs knockout ( KO ) mice showed significantly decreased response to stimulation with transforming growth factor-β ( TGF-β ) family molecules.( 3 ) AMSH-deficient mice exhibited postnatal growth, retardation and died between day 19 and 23. The neurons were defect in the subfield of hippocampus of AMSH-deficient mice.( 4 ) The total number of thymocytes were reduced in the transgenic mice expressing Graf40 mutant, whereas it was significantly increased in the double-negative thymocytes subset.