Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor
Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor
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DOI：
10.1073/pnas.0911755107
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发表时间：
2010-03-30
影响因子：
11.1
通讯作者：
Yasutomo, Koji
中科院分区：
文献类型：
--
作者：
Alam, Muhammad Shamsul;Maekawa, Yoichi;Yasutomo, Koji
CD4(+) 辅助 T (Th) 细胞分化为不同的效应细胞谱系，其特征在于其独特的细胞因子表达模式和功能。多个 Th 细胞群分泌 IL-22，有助于保护性和病理性炎症反应。尽管产生 IL-22 的 Th 细胞的分化是由芳烃受体 (AhR) 控制的，但我们对诱导 AhR 生理刺激物的调节机制知之甚少。在这里，我们表明Notch信号通过涉及AhR刺激的机制增强CD4(+)T细胞产生IL-22。即使在 STAT3 缺失的情况下，Notch 介导的 CD4+ T 细胞刺激也会增加 IL-22 的产生。 RBP-J缺陷小鼠的CD4(+) T细胞几乎没有能力通过T细胞受体介导的刺激产生IL-22。 RBP-J缺陷小鼠对ConA诱导的肝炎相关的有害免疫病理学高度敏感，且CD4+T细胞很少产生IL-22。外源性 IL-22 可以保护 RBP-J 缺陷小鼠免受刀豆蛋白 A 诱导的肝炎的影响。 Notch 信号传导促进 AhR 内源刺激物的产生，从而进一步增强 IL-22 的分泌。我们的研究确定了 Notch-AhR 轴可调节 IL-22 表达并微调免疫系统对炎症反应的控制。
CD4(+) helper T (Th) cells differentiate toward distinct effector cell lineages characterized by their distinct cytokine expression patterns and functions. Multiple Th cell populations secrete IL-22 that contributes to both protective and pathological inflammatory responses. Although the differentiation of IL-22-producing Th cells is controlled by the aryl hydrocarbon receptor (AhR), little is known about the regulatory mechanisms inducing physiological stimulators for AhR. Here, we show that Notch signaling enhances IL-22 production by CD4(+) T cells by a mechanism involving AhR stimulation. Notch-mediated stimulation of CD4(+) T cells increased the production of IL-22 even in the absence of STAT3. CD4(+) T cells from RBP-J-deficient mice had little ability to produce IL-22 through T cell receptor-mediated stimulation. RBP-J-deficient mice were highly susceptible to the detrimental immunopathology associated with ConA-induced hepatitis with little IL-22 production by CD4(+) T cells. Exogenous IL-22 protected RBP-J-deficient mice from ConA-induced hepatitis. Notch signaling promoted production of endogenous stimulators for AhR, which further augmented IL-22 secretion. Our studies identify a Notch-AhR axis that regulates IL-22 expression and fine-tunes immune system control of inflammatory responses.