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Naturally occurring T regulatory cells control airway hyperresponsiveness

天然存在的 T 调节细胞控制气道高反应性

基本信息

批准号：
7683378
负责人：
ERWIN William GELFAND
金额：
$ 48.67万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-17 至 2009-08-31
项目状态：
已结题

项目摘要

ABSTRACT In susceptible individuals, asthma is a complex disease characterized by heightened responses to relatively innocuous antigens encountered via the respiratory tract. In a shift in thinking away from simple imbalances in Th2 and Th1 responses, there is increasing evidence for a protective role for regulatory T cells in allergic disease where they exhibit control over effector Th1 and Th2 cells. Naturally-occurring CD4+CD25+Foxp3+ regulatory cells (nTregs) isolated from the lungs of naive mice and transferred intratracheally into sensitized recipients prior to challenge suppress all aspects of lung allergic responses including airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine production, and goblet cell metaplasia. Conversely, depletion of these cells with anti-CD25 enhanced all of these responses. Our data indicate that the suppressive phenotype of nTregs is dependent on CD8-MHC I interactions and their production of IL-10 and TGF¿. We will define the role of these nTregs in regulating mast cell-dependent and -independent AHR and whether they are responsible for the tolerant state induced by repeated allergen challenge. Using biochemical tools, genetic manipulation and in vitro and in vivo approaches, we will define the underlying mechanisms whereby CD8-MHC I interactions signal and maintain Foxp3 expression and the suppressive phenotype. We will also define how, in the absence of interaction with CD8 in recipient mice, the nTregs demonstrate plasticity, converting to an enhancing phenotype through production of Th2 cytokines. Since signaling through the glucocorticoid inducible tumor necrosis factor receptor (GITR) attenuates the suppressive phenotype, we will delineate the counter-regulatory signals provided through Foxp3 and GITR and the interplay between these two defining events that appear to govern the fate (suppressive or enhancing phenotype) of nTregs. For the first time, these studies will identify the indispensable role and mechanism whereby Foxp3+nTreg control the development of lung allergic responses in sensitized hosts exposed to allergen challenge. Elucidation of the molecular basis for the functional activation of nTregs and the underlying mechanisms dictating nTreg-mediated suppression or nTreg conversion to an enhancing phenotype will form the basis for the control of their function in diseases such as asthma.

摘要在易感个体中，哮喘是一种复杂的疾病，其特征在于对通过呼吸道遇到的相对无害的抗原的反应增强道。在思维从Th 2和Th 1反应的简单失衡转变中，越来越多的证据表明调节性T细胞在过敏性疾病中具有保护作用其中它们表现出对效应Th 1和Th 2细胞的控制。天然存在从未处理小鼠的肺分离的CD 4 + CD 25 + Foxp 3+调节细胞（nT细胞）和在激发前经皮转移至致敏受体中抑制所有肺过敏反应的方面，包括气道高反应性（AHR），气道高反应性（AHR），嗜酸性粒细胞增多、Th 2细胞因子产生和杯状细胞化生。相反，这些细胞与抗CD 25增强了所有这些反应。我们的数据表明， nT细胞抑制性表型依赖于CD 8-MHC I相互作用，产生IL-10和TGF β。我们将定义这些nTables在调节桅杆中的作用，细胞依赖性和非依赖性AHR以及它们是否负责耐受性AHR，由反复过敏原激发引起的状态。利用生物化学工具，操作和在体外和体内的方法，我们将定义的基础 CD 8-MHC I相互作用信号传导和维持Foxp 3表达的机制和抑制性表型。我们还将定义如何在没有相互作用的情况下与受体小鼠中的CD 8相比，nT细胞表现出可塑性，通过产生Th 2细胞因子增强表型。自从通过糖皮质激素诱导的肿瘤坏死因子受体（GITR）可减弱抑制表型，我们将描绘提供的反调节信号通过Foxp 3和GITR以及这两个定义事件之间的相互作用，似乎支配nTdR的命运（抑制或增强表型）。第一同时，这些研究将确定不可或缺的作用和机制， Foxp 3 +nTreg调控致敏宿主肺变态反应的发生暴露于过敏原挑战。功能性的分子基础的阐明 nTreg的激活和决定nTreg介导的抑制或nTreg转化为增强表型将形成免疫抑制的基础。控制它们在哮喘等疾病中的功能。