Gomez-Rodriguez Julio, Meylan Françoise, Handon Robin, Hayes Erika T, Anderson Stacie M, Kirby Martha R, Siegel Richard M, Schwartzberg Pamela L
National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892, USA.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
Nat Commun. 2016 Mar 3;7:10857. doi: 10.1038/ncomms10857.
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.
Th9细胞产生白细胞介素（IL）-9，这是一种与过敏性哮喘和自身免疫有关的细胞因子。我们在此表明，Itk是Th2免疫反应和哮喘发展所需的T细胞受体信号传导介质，是Th9分化的正向调节因子。在过敏性肺病模型中，Itk缺陷小鼠的肺部炎症减轻，T细胞和2型先天性淋巴细胞（ILC2）产生的IL-9减少，尽管ILC2的早期诱导正常。在体外，Itk(-/-) CD4(+) T细胞不产生IL-9，且干扰素调节因子4（IRF4）水平降低，IRF4是效应T细胞功能的关键转录因子。IL-2或组成型活性STAT5均可挽救IL-9和IRF4的表达，但NFATc1不能。STAT5结合Irf4启动子，证明了IL-2挽救弱活化T细胞的一种机制。Itk抑制也会降低人T细胞的IL-9表达，表明ITK是Th9诱导的关键调节因子。
