Smad2/3 and IRF4 Play a Cooperative Role in IL-9-Producing T Cell Induction
Smad2/3 and IRF4 Play a Cooperative Role in IL-9-Producing T Cell Induction
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DOI：
10.4049/jimmunol.1301276
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Tamiya, Taiga;Ichiyama, Kenji;Yoshimura, Akihiko
IL-9是一种多效性细胞因子，可调节自身免疫和过敏反应。Th9细胞可在体外通过转化生长因子-β刺激由初始T细胞或Th2细胞分化为Th9细胞。在这项研究中，我们使用T细胞特异性Smad2和Smad3缺陷小鼠，证明了Smad2和Smad3是T细胞产生IL-9所必需的。Smad2和Smad3也是诱导Il9转录的组蛋白修饰的转化生长因子-β信号的冗余必需的。尽管Smad2/3通过转化生长因子-β刺激被招募到IL9启动子，但它们不足以激活IL9启动子。通过对转录因子的筛选，我们发现干扰素调节因子4(IRF4)是Smad2/3介导的IL9启动子激活所必需的。此外，Smad2/3与IRF4在物理上相互作用，Smad2/3不与IL9启动子结合，也不能诱导IRF4缺陷的T细胞产生Th9。同样，IRF4在缺乏Smad2/3的情况下不能刺激IL9的转录，而转化生长因子-β以Smad2/3依赖的方式促进IRF4向IL9启动子的募集。我们认为Smad2/3和IRF4协同反式激活IL9启动子，通过诱导Th9细胞在调节变态反应性免疫反应中发挥重要作用。
IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-beta in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell-specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-beta signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-beta stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-beta enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells.