Expression of a constitutively active stat6 in vivo alters lymphocyte homeostasis with distinct effects in T and B cells
Expression of a constitutively active stat6 in vivo alters lymphocyte homeostasis with distinct effects in T and B cells
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DOI：
10.4049/jimmunol.170.7.3478
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发表时间：
2003-04-01
影响因子：
4.4
通讯作者：
Kaplan, MH
中科院分区：
文献类型：
--
作者：
Bruns, HA;Schindler, U;Kaplan, MH
IL-4是调节免疫应答和特应性发生的关键细胞因子。IL-4 R的参与激活多种信号传导途径，包括转录因子Stat 6。Stat 6缺陷小鼠证明了该因子在淋巴细胞增殖、基因表达和Th细胞分化中的重要性。最近，产生了一种突变型Stat 6（Stat 6VT），其转录活性不依赖于IL-4刺激。为了确定组成型活性Stat 6模拟IL-4刺激反应的能力，我们产生了在CD 2基因座控制区控制下表达Stat 6 VT的转基因小鼠，将表达限制在淋巴细胞群中。Stat 6VT转基因小鼠的表型与IL-4转基因小鼠相似，但不相同，这表明Stat 6非依赖性信号通路在体内产生一些IL-4应答中起关键作用。与非转基因小鼠相比，Stat 6在体内的组成型活性表达增加了IL-4诱导的基因的表面表达，并增加了IgG 1和IgE的血清水平。Stat 6VT表达增加体内和体外Th 2分化。Stat 6VT的表达也显著改变了外周淋巴细胞群的稳态，导致与非转基因同窝仔相比，CD 3（+）细胞减少，B220（+）细胞增加。改变的T和B细胞群体与转基因T细胞群体中的活化表型和增加的细胞死亡相关，但与B细胞群体无关。总之，这些结果表明，组成型活性Stat 6的表达对B和T淋巴细胞具有不同的作用。
IL-4 is a critical cytokine in the regulation of immune responses and genesis of atopy. Engagement of the IL-4R activates multiple signaling pathways, including the transcription factor Stat6. Stat6-deficient mice demonstrate the importance of this factor in lymphocyte proliferation, gene expression, and Th cell differentiation. Recently, a mutant Stat6 (Stat6VT) was generated that is transcriptionally active independent of IL-4 stimulation. To determine the ability of a constitutively active Stat6 to mimic IL-4-stimulated responses, we have generated transgenic mice expressing Stat6VT under control of the CD2 locus control region, restricting expression to lymphoid populations. The phenotype of Stat6VT transgenic mice is similar, but not identical, to IL-4 transgenic mice, suggesting a critical role for Stat6-independent signaling pathways in the generation of some IL-4 responses in vivo. The expression of a constitutively active Stat6 in vivo increases surface expression of IL-4-induced genes and increases serum levels of IgG1 and IgE, compared with nontransgenic mice. Stat6VT expression increases Th2 differentiation in vivo and in vitro. Stat6VT expression also dramatically alters homeostasis of peripheral lymphocyte populations resulting in decreased CD3(+) cells and increased B220(+) cells, compared with nontransgenic littermates. Altered T and B cell populations correlate with an activated phenotype and increased cell death in transgenic T cell, but not B cell, populations. Together these results suggest that expression of a constitutively active Stat6 has distinct effects on B and T lymphocytes.