Naturally Occurring T Regulatory Cells Control Airway Hyperresponsiveness

描述（由申请人提供）：在易感个体中，哮喘是一种复杂的疾病，其特征是对通过呼吸道遇到的相对无害的抗原的反应增强。从Th2和Th1反应的简单不平衡的想法转变，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Th1和Th2细胞的控制。自然产生的CD4+CD25+Foxp3+调节细胞（nTregs）从幼年小鼠的肺中分离出来，并在激发前经气管内转移到致敏受体中，可抑制肺过敏反应的各个方面，包括气道高反应性（AHR）、气道嗜酸性粒细胞增加、Th2细胞因子产生和杯状细胞化生。相反，用抗cd25耗尽这些细胞会增强所有这些反应。我们的数据表明，nTregs的抑制表型依赖于CD8- MHC I相互作用及其IL-10和TGF2的产生。在缺乏CD8-MHC I相互作用的情况下，nTregs的表型转化为促进肺部过敏反应发展的表型，并与IL-13产生增加和Foxp3表达降低相关。相比之下，通过糖皮质激素诱导的肿瘤坏死因子受体（GITR）的信号传导减弱了抑制性表型。我们将确定这些nTregs在调节肥大细胞依赖性和非依赖性AHR中的作用，以及它们是否负责反复过敏原攻击诱导的耐受状态。利用生化工具、遗传操作以及体外和体内方法，我们将定义CD8-MHC I相互作用信号传导和维持Foxp3表达和抑制表型的潜在机制，并确定通过gitr - gitr配体的信号传导如何减弱抑制、破坏和转化nTregs到以Th2细胞因子产生为特征的增强表型。在这些方法中，我们将描述通过Foxp3和GITR提供的反调控信号，以及这两个决定性事件之间的相互作用，这些事件似乎决定了nTregs的命运（抑制或增强表型）。这些研究将首次确定Foxp3+nTregs在致敏宿主暴露于过敏原挑战时控制肺部过敏反应发展的不可或缺的作用和机制。阐明nTreg功能激活的分子基础和决定nTreg介导的抑制或nTreg转化为增强表型的潜在机制将为控制其在哮喘等疾病中的功能奠定基础。公共卫生相关性：哮喘现在折磨着3000多万美国人，尽管引进了新的治疗方法，发病率和死亡率仍在继续增加。如果我们要影响这种疾病，就需要更好地了解哮喘进展的机制，描述调节途径，并确定新的策略。该建议提出了可能调节气道高反应性和炎症的新途径，具有揭示新的重要治疗策略的潜力。

DESCRIPTION (provided by applicant): 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 TGF2. In the absence of CD8-MHC I interactions, the phenotype of the nTregs converts to one which enhances the development of lung allergic responses, and is associated with increased IL-13 production and decreased Foxp3 expression. By contrast, signaling through the glucocorticoid inducible tumor necrosis factor receptor (GITR) attenuates the suppressive phenotype. 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, and determine how signaling through GITR-GITR-ligand attenuates suppression, subverting and converting nTregs to an enhancing phenotype, characterized by Th2 cytokine production. In these approaches, 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+nTregs 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. PUBLIC HEALTH RELEVANCE: Asthma now afflicts more than 30 million Americans and despite the introduction of new therapies, morbidity and mortality continue to increase. If we are to impact this disease, a greater understanding of the mechanisms underlying asthma progression, delineation of the regulatory pathways, and identification of new strategies are required. This proposal addresses novel pathways that may regulate airway hyperresponsiveness and inflammation, with the potential of revealing novel and important therapeutic strategies.