Targeting allergen to FcgammaRI reveals a novel T(H)2 regulatory pathway linked to thymic stromal lymphopoietin receptor.
Targeting allergen to FcgammaRI reveals a novel T(H)2 regulatory pathway linked to thymic stromal lymphopoietin receptor.
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DOI：
10.1016/j.jaci.2009.10.027
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发表时间：
2010-01
影响因子：
14.2
通讯作者：
Woodfolk, Judith A
中科院分区：
文献类型：
--
作者：
Hulse, Kathryn E;Reefer, Amanda J;Engelhard, Victor H;Patrie, James T;Ziegler, Steven F;Chapman, Martin D;Woodfolk, Judith A
分子H22-Fel d1靶向树突状细胞上的猫致敏原FcγRI，由于其t细胞调节特性，具有治疗猫过敏的潜力。探讨H22-Fel d1诱导的t细胞反应是否在促th2细胞因子TSLP的存在下发生改变。研究对象是有或没有特应性皮炎的猫过敏受试者。在TSLP存在或不存在的情况下，用H22-Fel d1诱导单核细胞衍生的树突状细胞，并通过流式细胞术分析产生的t细胞细胞因子库。在Fc受体信号分子抑制剂存在或不存在的情况下，流式细胞术检测了H22-Fel d1调节树突状细胞TSLP受体表达的能力。令人惊讶的是，与特应性状态无关，单独的TSLP是Th2反应的弱诱导剂；然而，树突状细胞与TSLP和H22-Fel d1共引物选择性地和协同地放大了高度特应性受试者的Th2反应。这种作用与OX40配体无关，指向非常规的tslp介导途径。在H22-Fel d1引发的特应性树突状细胞中，TSLP受体的表达上调是通过fc γ γ - ri相关信号通路调控的，包括src相关酪氨酸激酶和Syk，以及下游分子pi3激酶。抑制H22-Fel d1引发的TSLP受体上调可阻断TSLP介导的Th2反应。一种将fc γ - ri信号与TSLP受体上调联系起来的新型Th2调控途径的发现及其介导的TSLP效应对受体靶向过敏原疫苗的有效性提出了质疑。本研究确立了Fc受体连接在促进与变应性疾病相关的tslp介导的Th2反应中的关键作用。特异应性树突状细胞在变应原连接Fc受体时能够有效上调TSLP受体。这些发现表明，靶向Fc受体的树突状细胞疫苗可以通过增强TSLP的作用来放大th2驱动的炎症反应。
The molecule H22-Fel d 1, which targets cat allergen to FcγRI on dendritic cells, has the potential to treat cat allergy owing to its T-cell modulatory properties. To investigate whether the T-cell response induced by H22-Fel d 1 is altered in the presence of the Th2-promoting cytokine, TSLP. Studies were performed in cat-allergic subjects with and without atopic dermatitis. Monocyte-derived dendritic cells were primed with H22-Fel d 1 in the presence or absence of TSLP and the resulting T-cell cytokine repertoire was analyzed by flow cytometry. The capacity for H22-Fel d 1 to modulate TSLP receptor expression on dendritic cells was examined by flow cytometry in the presence or absence of inhibitors of Fc receptor signaling molecules. Surprisingly, TSLP alone was a weak inducer of Th2 responses irrespective of atopic status; however, dendritic cells co-primed with TSLP and H22-Fel d 1 selectively and synergistically amplified Th2 responses in highly atopic subjects. This effect was OX40 ligand-independent pointing to an unconventional TSLP-mediated pathway. Expression of TSLP receptor was upregulated on atopic dendritic cells primed with H22-Fel d 1 through a pathway regulated by FcγRI-associated signaling components, including src related tyrosine kinases and Syk, as well as the downstream molecule, PI3-kinase. Inhibition of TSLP receptor upregulation triggered by H22-Fel d 1 blocked TSLP-mediated Th2 responses. Discovery of a novel Th2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines. This study establishes a pivotal role for Fc receptor ligation in promoting TSLP-mediated Th2 responses associated with allergic disease. Atopic dendritic cells are equipped to efficiently upregulate TSLP receptor upon Fc receptor ligation by allergen. These findings suggest that dendritic cell-based vaccines that target Fc receptors could amplify Th2-driven inflammatory responses by potentiating the effects of TSLP.