GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma.
GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma.
复制标题
GITR信号传导通过在哮喘的小鼠模型中增强Th2细胞活性来增强气道高反应性。
DOI：
10.1186/1465-9921-10-93
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发表时间：
2009-10-07
影响因子：
5.8
通讯作者：
Nawijn MC
中科院分区：
文献类型：
--
作者：
Motta AC;Vissers JL;Gras R;Van Esch BC;Van Oosterhout AJ;Nawijn MC
过敏性哮喘的特征在于气道高反应性（AHR）和气道的过敏性炎症，由过敏原特异性Th 2细胞驱动。哮喘表型，尤其是AHR对肺中调节性T（Treg）细胞的存在和活性敏感。已知糖皮质激素诱导的肿瘤坏死因子受体（GITR）对效应CD 4 + T细胞具有共刺激功能，使得这些细胞对Treg抑制不敏感。然而，GITR信号传导对极化的Th 1和Th 2细胞效应子功能的影响尚未得到充分证实。我们试图评估GITR信号对完全分化的Th 1和Th 2细胞的影响，并确定在过敏原激发时GITR激活对Th 2驱动的哮喘小鼠模型中AHR和气道炎症的影响。在体外将CD 4 + CD 25-细胞极化为Th 1和Th 2效应细胞，并在GITR激动性抗体存在下再刺激以评估对IFNγ和IL-4产生的影响。为了评估GITR刺激对小鼠哮喘模型中AHR和过敏性炎症的影响，在存在或不存在GITR激动剂抗体的情况下，将BALB/c小鼠对OVA致敏，然后进行气道激发。GITR参与增强了体外CD 3/CD 28刺激的Th 2细胞而不是Th 1细胞的细胞因子释放。在小鼠哮喘模型中，激发时GITR触发诱导增强的气道高反应性、血清IgE和离体Th 2细胞因子释放，但不增加BAL嗜酸性粒细胞增多。GITR在体外对完全分化的Th 1和Th 2细胞的细胞因子释放发挥不同的作用，增强Th 2而不是Th 1细胞因子的产生。在我们的哮喘小鼠模型中也观察到这种对Th 2效应子功能的影响，导致AHR、血清IgE应答和Th 2细胞因子产生增强。这是第一份报告显示GITR激活对极化的初级Th 1和Th 2群体细胞因子产生的影响，以及该途径与哮喘小鼠模型中AHR的相关性。我们的数据提供了关于GITR信号传导的作用模式的关键信息，这是一种目前正在考虑进行治疗干预的途径。
Allergic asthma is characterized by airway hyperresponsiveness (AHR) and allergic inflammation of the airways, driven by allergen-specific Th2 cells. The asthma phenotypes and especially AHR are sensitive to the presence and activity of regulatory T (Treg) cells in the lung. Glucocorticoid-induced tumor necrosis factor receptor (GITR) is known to have a co-stimulatory function on effector CD4+ T cells, rendering these cells insensitive to Treg suppression. However, the effects of GITR signaling on polarized Th1 and Th2 cell effector functions are not well-established. We sought to evaluate the effect of GITR signaling on fully differentiated Th1 and Th2 cells and to determine the effects of GITR activation at the time of allergen provocation on AHR and airway inflammation in a Th2-driven mouse model of asthma. CD4+CD25- cells were polarized in vitro into Th1 and Th2 effector cells, and re-stimulated in the presence of GITR agonistic antibodies to assess the effect on IFNγ and IL-4 production. To evaluate the effects of GITR stimulation on AHR and allergic inflammation in a mouse asthma model, BALB/c mice were sensitized to OVA followed by airway challenges in the presence or absence of GITR agonist antibodies. GITR engagement potentiated cytokine release from CD3/CD28-stimulated Th2 but not Th1 cells in vitro. In the mouse asthma model, GITR triggering at the time of challenge induced enhanced airway hyperresponsiveness, serum IgE and ex vivo Th2 cytokine release, but did not increase BAL eosinophilia. GITR exerts a differential effect on cytokine release of fully differentiated Th1 and Th2 cells in vitro, potentiating Th2 but not Th1 cytokine production. This effect on Th2 effector functions was also observed in vivo in our mouse model of asthma, resulting in enhanced AHR, serum IgE responses and Th2 cytokine production. This is the first report showing the effects of GITR activation on cytokine production by polarized primary Th1 and Th2 populations and the relevance of this pathway for AHR in mouse models for asthma. Our data provides crucial information on the mode of action of the GITR signaling, a pathway which is currently being considered for therapeutic intervention.
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CD4+ CD25+调节T细胞体内转移后气道炎症和过度反应性的分辨率取决于白介素10。
DOI：
10.1084/jem.20051166
发表时间：
2005-12-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1152/ajplung.00521.2007
发表时间：
2009-03-01
影响因子：
4.9
作者：
Burchell, Jennifer T.;Wikstrom, Matthew E.;Turner, Debra J.
通讯作者：
Turner, Debra J.
影响因子：
4.4
作者：
Kohm, AP;Williams, JS;Miller, SD
通讯作者：
Miller, SD
影响因子：
4.4
作者：
Ji, HB;Liao, GX;Terhorst, C
通讯作者：
Terhorst, C
DOI：
10.1084/jem.20040116
发表时间：
2004-07-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Muriglan SJ;Ramirez-Montagut T;Alpdogan O;Van Huystee TW;Eng JM;Hubbard VM;Kochman AA;Tjoe KH;Riccardi C;Pandolfi PP;Sakaguchi S;Houghton AN;Van Den Brink MR
通讯作者：
Van Den Brink MR