Mechanism of T Cell Resistance against Treg-mediated suppression in asthma

摘要 T细胞在哮喘和其他过敏性疾病的发病机制中的重要性是 无可争辩。T细胞反应的程度受到多种动态平衡的严格控制。 机械装置。T调节细胞(Tregs)是一种主要的体内平衡机制。Tregs是 能够逆转动物模型中的过敏性炎症。人类Tregs的数量 据报道，包括哮喘在内的过敏性疾病的发病率很低或正常。在预赛中 我们观察到哮喘患者的T细胞对Treg介导的免疫耐药 压制。哮喘T细胞表现为增殖能力增强，存活时间延长， 这与ERK1/2和JNK信号通路的激活增强有关。 抑制ERK1/2而不是JNK使哮喘T细胞对Tregs易感。基于 这些初步结果我们假设T细胞对Treg介导的 抑制在维持慢性哮喘Th2型炎症中起重要作用， ERK1/2及其下游效应子JunB参与了这种抗性。我们将测试 这一假设在2个具体目标中-1)。定义和表征T细胞对 调节性T细胞介导的哮喘抑制。2)。研究ERK1/2信号转导途径的作用 介导T细胞耐药的途径。在特定目标#1下，我们将检测T细胞耐药性 在过敏性哮喘患者、健康人和疾病对照组中，建立其临床相关性 和疾病的关联性。我们还将研究细胞因子和共刺激的作用。 分子在建立T细胞抵抗中的作用。在具体目标#2下，我们将检查是否 ERK1/2信号转导模块通过诱导 MEK1依赖的正反馈环与MKP3依赖的负反馈抑制 循环播放。我们将研究ERK1/2和JunB与人类哮喘T细胞抵抗的相关性。 在慢性哮喘小鼠模型中使用可诱导基因敲除和转基因 接近了。这项提议之所以重要，是因为它解决了 哮喘的慢性炎症。T细胞抵抗Treg介导的抑制是一种 相对较新的观察结果，可能对慢性阻塞性肺疾病的持续性炎症很重要 哮喘以外的疾病。对T细胞耐药性的分子理解可能有助于 治疗哮喘和其他过敏性疾病的新疗法。

ABSTRACT The importance of T cells in the pathogenesis of asthma and other allergic diseases is undisputed. The extent of the T cell response is tightly controlled by a variety of homeostatic mechanisms. T regulatory cells (Tregs) represent a major homeostatic mechanism. Tregs are capable of reversing allergic inflammation in animal models. The number of Tregs in human allergic diseases including asthma has been reported to be low or normal. In preliminary studies we observed that T cells from asthmatic patients are resistant to Treg-mediated suppression. Asthmatic T cells manifest increased proliferative capacity and prolonged survival, which was associated with heightened activation of ERK1/2 and JNK signaling pathways. Inhibition of ERK1/2 but not JNK makes asthmatic T cells susceptible to Tregs. Based upon these preliminary results we hypothesize that T cell resistance against Treg-mediated suppression plays an important role in sustaining the Th2-type inflammation in chronic asthma, and that ERK1/2 and its downstream effector JunB contributes to this resistance. We will test this hypothesis in 2 specific aims-1). Define and characterize T cell resistance against regulatory T cell-mediated inhibition in asthma. 2). Investigate the role of the ERK1/2 signaling pathway in mediating T cell resistance. Under specific aim #1 we will examine T cell resistance in allergic asthmatic patients, and healthy and disease controls, establish its clinical correlation and disease relevance. We will also examine the role of cytokines and co-stimulatory molecules in establishing T cell resistance. Under specific aim #2 we will examine whether the ERK1/2 signaling module establishes a self-sustaining mechanism through the induction of a MEK1-dependent positive feedback loop and inhibition of a MKP3-dependent negative feedback loop. We will study the relevance of ERK1/2 and JunB for T cell resistance in human asthma and in a mouse model of chronic asthma using inducible gene knockout and transgenic approaches. The proposal is important because it addresses the mechanism of persistence of chronic inflammation in asthma. T cell resistance against Treg-mediated suppression is a relatively novel observation and is likely to be important for persistent inflammation in chronic diseases beyond asthma. A molecular understanding of T cell resistance could help develop novel therapeutic modalities for treatment of asthma and other allergic diseases.