Jagged1 on Dendritic Cells and Notch on CD4+ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production
Jagged1 on Dendritic Cells and Notch on CD4+ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production
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DOI：
10.4049/jimmunol.0900692
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发表时间：
2009-09-01
影响因子：
4.4
通讯作者：
Gelfand, Erwin W.
中科院分区：
文献类型：
--
作者：
Okamoto, Masakazu;Matsuda, Hiroyuki;Gelfand, Erwin W.
Notch配体Jagged 1和Notch与Th 2分化有关，但它们在体内启动IL-4产生和Th 2分化以及过敏性气道反应发展中的作用尚未确定。在这项研究中，我们表明，锯齿状蛋白1上调骨髓来源的树突状细胞（BMDCs）与过敏原脉冲和这些BMDCs过敏原挑战前的转移诱导气道高反应性（AHR）和嗜酸性粒细胞气道炎症。用γ-分泌酶抑制剂（GSI）处理CD 4（+）T细胞，抑制Notch信号传导，当细胞与变应原脉冲的、表达Jagged 1的BMDCs共培养时，细胞因子的产生减少，而在变应原脉冲的BMDCs转移后，IL-4缺陷的BMDCs，细胞因子的产生减少。GSI处理的初始CD 4（+）T细胞的IL-4（-/-）受体在用变应原攻击时产生较低水平的AHR、减少的嗜酸性粒细胞数量和较低的Th 2细胞因子水平。在体内用Jagged 1-Fc处理野生型小鼠增强了AHR和气道炎症，而在转移CD 4（+）T细胞之前将用Jagged 1小干扰RNA（siRNA）细胞转染的BMDC转移到WT或IL-4（-/）-小鼠中导致AHR、炎症和Th 2细胞因子降低，表明Jagged 1在APC上表达的关键作用。这些数据确定了CD 4（+）T细胞上的Notch和APC上的Jaggedl之间的相互作用在启动IL-4产生和Th 2分化以发展AHR和过敏性气道炎症中的重要作用。免疫学杂志，2009，183：2995-3003.
Jagged1, a Notch ligand, and Notch have been implicated in Th2 differentiation, but their role in initiating IL-4 production and Th2 differentiation in vivo and the development of allergic airway responses has not been defined. In this study, we show that Jagged1 is up-regulated on bone marrow-derived dendritic cells (BMDCs) pulsed with allergen and that the transfer of these BMDCs before allergen challenge induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation. Treatment of CD4(+) T cells with a gamma-secretase inhibitor (GSI), which inhibits Notch signaling, resulted in decreased cytokine production when the cells were cocultured with allergen-pulsed, Jagged1-expressing BMDCs and, after the transfer of allergen-pulsed BMDCs, IL-4-deficient (IL-4(-/-)) recipients of GSI-treated naive CD4(+) T cells developed lower levels of AHR, reduced numbers of eosinophils, and lower Th2 cytokine levels when challenged with allergen. In vivo treatment of wild-type mice with Jagged1-Fc enhanced AHR and airway inflammation, whereas the transfer of BMDC transfected with Jagged1 small interfering RNA (siRNA) cells into WT or IL-4(-/)- mice before transfer of CD4(+) T cells resulted in decreased AHR, inflammation, and Th2 cytokines, indicating the critical role for Jagged1 expression on APCs. These data identify the essential role of the interactions between Notch on CD4(+) T cells and Jaggedl on APCs in the initiation of IL-4 production and Th2 differentiation for the development of AHR and allergic airway inflammation. The Journal of Immunology, 2009, 183: 2995-3003.