WSX-1 over-expression in CD4+ T cells leads to hyperproliferation and cytokine hyperproduction in response to TCR stimulation
WSX-1 over-expression in CD4+ T cells leads to hyperproliferation and cytokine hyperproduction in response to TCR stimulation
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DOI：
10.1093/intimm/dxh268
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发表时间：
2005-07-01
影响因子：
4.4
通讯作者：
Yoshida, H
中科院分区：
文献类型：
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作者：
Takeda, A;Hamano, S;Yoshida, H
WSX-1是IL-27R的一个组成部分。对WSX-1敲除（WSX-1(-/-)）小鼠的分析表明，IL-27/WSX-1信号传导对于T(h)1反应的正常发展至关重要，WSX-1可以抑制细胞活化和促炎细胞因子的产生。我们在T细胞特异性CD2启动子的控制下产生了过表达WSX-1基因的转基因小鼠（WSX-1 Tg小鼠）。出乎意料的是，与来自WSX-1（-/-）小鼠的活化CD4(+) T细胞一样，来自WSX-1 Tg小鼠的活化CD4(+) T细胞也表现出增殖增加、IL-2产生增加和活化标记物表面表达上调的现象。在WSX-1 Tg CD4(+) T细胞中，il -27介导的STAT1酪氨酸磷酸化也增强，但STAT3激活正常。外源性IL-27支持野生型CD4(+) T细胞的增殖，抑制WSX-1 Tg细胞的增殖。在T(h)1极化条件下，WSX-1过表达增加了T(h)1极化CD4(+) T细胞中ifn - γ的产生，但也促进了T(h)1极化条件下T(h)2细胞因子的产生。重要的是，在T(h)2极化条件下，WSX-1过表达未能抑制T(h)2细胞因子的产生。在注射Con a的WSX-1 Tg小鼠体内也观察到细胞因子的过量产生。我们的数据表明WSX-1在调节T细胞对TCR刺激的反应性中起着关键作用，并且IL-27R参与下游STAT1/STAT3激活的正确平衡对于IL-27的生理功能至关重要。
WSX-1 is a component of the IL-27R. Analyses of WSX-1 knockout (WSX-1(-/-)) mice have shown that IL-27/WSX-1 signaling is essential for the proper development of T(h)1 responses and that WSX-1 can suppress cellular activation and pro-inflammatory cytokine production. We have generated transgenic mouse lines over-expressing the WSX-1 gene under the control of the T cell-specific CD2 promoter (WSX-1 Tg mice). Unexpectedly, like activated CD4(+) T cells from WSX-1(-/-) mice, activated CD4(+) T cells from WSX-1 Tg mice showed increased proliferation, augmented IL-2 production and up-regulated surface expression of activation markers. IL-27-mediated tyrosine phosphorylation of STAT1 was also enhanced in WSX-1 Tg CD4(+) T cells, but STAT3 activation was normal. Exogenous IL-27 supported the proliferation of wild-type CD4(+) T cells but suppressed that of WSX-1 Tg cells. WSX-1 over-expression increased IFN-gamma production in T(h)1-polarized CD4(+) T cells, but also promoted T(h)2 cytokine production under T(h)1-polarizing conditions. Importantly, WSX-1 over-expression failed to suppress T(h)2 cytokine production under T(h)2-polarizing conditions. Cytokine hyperproduction was also observed in vivo in WSX-1 Tg mice injected with Con A. Our data suggest that WSX-1 plays a pivotal role in regulating T cell responsiveness to TCR stimulation and that the correct balance of STAT1/STAT3 activation downstream of IL-27R engagement is crucial for the physiological function of IL-27.