Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1.
Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1.
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DOI：
10.4049/jimmunol.0900124
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Li L
中科院分区：
文献类型：
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作者：
Maitra U;Davis S;Reilly CM;Li L
宿主免疫应答受到Th 17和T调节（Treg）细胞的相反作用的精细调节。Treg细胞有助于抑制炎症过程，Th 17细胞促进免疫激活的各个方面。Th细胞的分化依赖于刺激物的独特组合和随后的多种转录因子的激活。特别地，NFAT和Smad 3的协同激活导致Treg细胞的诱导，而STAT 3和Smad 3之间的协同作用转换为Th 17细胞的诱导。我们先前已经表明IL-1受体相关激酶1（IRAK-1）选择性地激活STAT 3并使NFAT失活。生理学研究表明，IRAK-1−/−小鼠可以防止发生各种炎症性疾病，包括实验性自身免疫性脑脊髓炎和机制不明的动脉粥样硬化。在这项研究中，我们证明了IRAK-1在Th 17和Treg细胞的分化中起着关键的调节作用。在用TCR激动剂和TGFβ刺激后，IRAK-1−/− CD 4 Th细胞显示核NFATc 2水平升高，NFATc 2和Smad 3的相互作用增加，导致Treg细胞的关键标志物Foxp 3表达增加。IRAK-1−/−小鼠具有组成性较高的Treg细胞群体。相反，当用TCR激动剂与IL-6和TGF-β共同刺激时，与野生型细胞相比，IRAK-1−/− CD 4 Th细胞表现出减弱的STAT 3 Ser 727磷酸化和降低的IL-17和RORγt表达。相应地，IRAK-1缺失导致急性和慢性炎症小鼠模型中IL-17表达降低和炎症反应减弱。我们的数据为IRAK-1−/−小鼠的抗炎表型提供了机制解释。
Host immune responses are finely regulated by the opposing effects of Th17 and T regulatory (Treg) cells. Treg cells help to dampen inflammatory processes and Th17 cells facilitate various aspects of immune activation. The differentiation of Th cells depends on a unique combination of stimulants and subsequent activation of diverse transcription factors. In particular, cooperative activation of NFAT and Smad3 leads to the induction of Treg cells, and cooperation among STAT3 and Smad3 switches to the induction of Th17 cells. We have previously shown that the IL-1 receptor associated kinase 1 (IRAK-1) selectively activates STAT3 and inactivates NFAT. Physiological studies have shown that IRAK-1−/− mice are protected from developing various inflammatory diseases, including experimental autoimmune encephalomyelitis and atherosclerosis with unknown mechanism. In this study, we demonstrate that IRAK-1 plays a critical modulatory role in the differentiation of Th17 and Treg cells. Following stimulation with TCR agonists and TGFβ, IRAK-1−/− CD4 Th cells display elevated nuclear NFATc2 levels and increased interaction of NFATc2 and Smad3, resulting in increased expression of Foxp3, a key marker for Treg cells. IRAK-1−/− mice have constitutively higher populations of Treg cells. In contrast, when stimulated with TCR agonists together with IL-6 and TGF-β, IRAK-1−/− CD4 Th cells exhibit attenuated STAT3 Ser727 phosphorylation and reduced expression of IL-17 and RORγt compared with wild-type cells. Correspondingly, IRAK-1 deletion results in decreased IL-17 expression and dampened inflammatory responses in acute and chronic inflammatory mice models. Our data provides mechanistic explanation for the anti-inflammatory phenotypes of IRAK-1−/− mice.