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

• 批准号: 7729164
• 负责人: ERWIN William GELFAND
• 金额: $ 45.89万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729164
• 关键词: Address; Adoptive Transfer; Allergens; Allergic; American; Antigens; Asthma; Attenuated; Biochemical; CD8B1 gene; Cells; Complex; Data; Disease; Eosinophilia; Event; Exercise; Exhibits; Glucocorticoids; Goblet Cells; In Vitro; Individual; Inflammation; Interleukin-10; Interleukin-13; Ligands; Lung; Maintenance; Mediating; Metaplasia; Molecular; Morbidity - disease rate; Mucous body substance; Mus; Pathway interactions; Phenotype; Production; Regulation; Regulatory Pathway; Respiratory System; Respiratory tract structure; Role; Signal Transduction; Source; Surface; T-Lymphocyte; Th2 Cells; Therapeutic; Thinking; Time Study; Tumor Necrosis Factor Receptor; airway hyperresponsiveness; airway inflammation; base; cytokine; functional outcomes; genetic manipulation; in vivo; lung development; mast cell; mortality; novel; programs; public health relevance; response; tool

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.

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。在思维从Th 2和Th 1应答的简单失衡转变中，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。天然存在的CD 4 + CD 25 + Foxp 3+调节细胞（nTCLs）从幼稚小鼠的肺中分离并在激发前经气管内转移到致敏受体中，抑制肺过敏反应的所有方面，包括气道高反应性（AHR）、气道嗜酸性粒细胞增多、Th 2细胞因子产生和杯状细胞化生。相反，用抗CD 25耗竭这些细胞增强了所有这些应答。我们的数据表明，nT细胞的抑制性表型依赖于CD 8- MHC I相互作用及其产生的IL-10和TGF-2。在不存在CD 8-MHC I相互作用的情况下，nT细胞的表型转化为增强肺过敏反应发展的表型，并与IL-13产生增加和Foxp 3表达减少相关。相比之下，通过糖皮质激素诱导的肿瘤坏死因子受体（GITR）的信号转导减弱了抑制性表型。我们将确定这些nTbR在调节肥大细胞依赖性和非依赖性AHR中的作用，以及它们是否负责由反复过敏原挑战诱导的耐受状态。使用生化工具，遗传操作和在体外和体内的方法，我们将定义潜在的机制，CD 8-MHC I相互作用信号和维持Foxp 3的表达和抑制表型，并确定如何通过GITR-GITR-配体信号减弱抑制，颠覆和转换nT细胞的增强表型，其特征在于Th 2细胞因子的产生。在这些方法中，我们将描述通过Foxp 3和GITR提供的反调节信号，以及这两个定义事件之间的相互作用，这两个事件似乎决定了nT细胞的命运（抑制或增强表型）。这些研究将第一次确定Foxp 3 + nTcR在暴露于过敏原激发的致敏宿主中控制肺过敏反应发展的不可或缺的作用和机制。阐明nTreg功能活化的分子基础和决定nTreg介导的抑制或nTreg转化为增强表型的潜在机制将形成控制其在疾病如哮喘中的功能的基础。公共卫生相关性：哮喘现在困扰着3000多万美国人，尽管引入了新的治疗方法，但发病率和死亡率继续增加。如果我们要影响这种疾病，需要更好地了解哮喘进展的机制，描绘调控途径，并确定新的策略。该提案提出了可能调节气道高反应性和炎症的新途径，具有揭示新的和重要的治疗策略的潜力。