Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4.
Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4.
复制标题
DOI：
10.1038/ncomms10857
复制
发表时间：
2016-03-03
影响因子：
16.6
通讯作者：
Schwartzberg PL
中科院分区：
文献类型：
--
作者：
Gomez-Rodriguez J;Meylan F;Handon R;Hayes ET;Anderson SM;Kirby MR;Siegel RM;Schwartzberg PL
Th 9细胞产生白细胞介素（IL）-9，一种与过敏性哮喘和自身免疫有关的细胞因子。在这里，我们表明，Itk，介导的T细胞受体信号所需的Th 2免疫反应和哮喘的发展，是一个积极的调节Th 9分化。在过敏性肺病模型中，Itk缺陷小鼠显示出减少的肺部炎症和T细胞和先天淋巴2型细胞（ILC 2）产生的IL-9，尽管ILC 2的早期诱导正常。在体外，Itk−/− CD 4 + T细胞不产生IL-9，并且IRF 4（干扰素调节因子4）水平降低，IRF 4是效应T细胞功能的关键转录因子。IL-9和IRF 4的表达都被IL-2或组成型激活的STAT 5所拯救，而不是NFATc 1。STAT 5结合Irf 4启动子，证明了IL-2拯救弱活化T细胞的一种机制。Itk抑制还降低人T细胞的IL-9表达，暗示ITK是Th 9诱导的关键调节因子。 Tec家族酪氨酸激酶Itk是体内最佳Th 2应答所必需的T细胞受体的组分。在这里，作者在人类细胞和小鼠模型中表明，Itk也是产生IL-9所必需的，IL-9是过敏性哮喘的重要贡献者。
Th9 cells produce interleukin (IL)-9, a cytokine implicated in allergic asthma and autoimmunity. Here we show that Itk, a mediator of T cell receptor signalling required for Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation. In a model of allergic lung disease, Itk-deficient mice show reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, Itk−/− CD4+ T cells do not produce IL-9 and have reduced levels of IRF4 (Interferon Regulator Factor 4), a critical transcription factor for effector T cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or constitutively active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, demonstrating one mechanism by which IL-2 rescues weakly activated T cells. Itk inhibition also reduces IL-9 expression by human T cells, implicating ITK as a key regulator of Th9 induction. The Tec family tyrosine kinase, Itk, is a component of the T-cell receptor essential for optimal Th2 responses in vivo. Here the authors show in human cells and mouse models that Itk is also needed for the production of IL-9, an important contributor to allergic asthma.