The basis for TCR-mediated regulation of the IL-2 receptor α chain gene:: role of widely separated regulatory elements
The basis for TCR-mediated regulation of the IL-2 receptor α chain gene:: role of widely separated regulatory elements
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DOI：
10.1093/emboj/cdf321
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发表时间：
2002-06-17
期刊：
影响因子：
11.4
通讯作者：
Leonard, WJ
中科院分区：
文献类型：
--
作者：
Kim, HP;Leonard, WJ
白细胞介素-2受体α（IL-2 R α）链是高亲和力IL-2受体的组分，因此是淋巴细胞增殖的关键调节因子。谱系限制性和激活依赖性IL-2 R α转录由四个上游正调控区（PRR）和一个下游PRR控制。我们现在证明，T细胞受体（TCR）的反应需要上游序列和内含子区，PRRIV，以前确定为IL-2的反应元件。尽管IL-2反应性需要Stat 5和HMG-I（Y）结合，PRRIV的TCR反应性需要两个AP-1-和两个NFAT-结合位点，其在体外和体内结合Jun、Fos和NFAT家族成员。此外，在来自表达显性阴性c-jun构建体的转基因小鼠或用环孢菌素A治疗后的T淋巴细胞中，IL-2 R α诱导受损。因此，我们的数据表明A-P-1和NFAT蛋白对于TCR诱导的IL-2 R α表达都具有重要作用，并建立了上游和内含子序列都介导IL-2 R α基因的TCR反应性。此外，我们的数据揭示了TCR介导的IL-2和IL-2 R α基因上调之间先前未被认识到的联系。
The interleukin-2 receptor alpha (IL-2Ralpha) chain is a component of high-affinity IL-2 receptors and thus is a key regulator of lymphocyte proliferation. Lineage-restricted and activation-dependent IL-2Ralpha transcription is controlled by four upstream positive regulatory regions (PRRs) and one downstream PRR. We now demonstrate that T-cell receptor (TCR) responsiveness requires both upstream sequences and an intronic region, PRRIV, previously identified as an IL-2 response element. Whereas IL-2 responsiveness requires Stat5 and HMG-I(Y) binding, TCR responsiveness of PRRIV requires two AP-1- and two NFAT-binding sites that bind Jun, Fos and NFAT family members in vitro and in vivo. Moreover, IL-2Ralpha induction is impaired in T lymphocytes from transgenic mice expressing a dominant-negative c-jun construct, or following treatment with cyclosporin A. Thus, our data indicate an important role for both A-P-1 and NFAT proteins for TCR-induced IL-2Ralpha expression and establish that both upstream and intronic sequences mediate TCR responsiveness of the IL-2Ralpha gene. Moreover, our data reveal a previously unappreciated link between the TCR-mediated upregulation of the IL-2 and IL-2Ralpha genes.