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发病机制中的重要性是 无可争议T细胞反应的程度受到多种稳态调节因子的严格控制。 机制等调节性T细胞（Tlymphocytes，Tlymphocytes）是一种重要的体内平衡机制。treg是 能够逆转动物模型中的过敏性炎症。人体内的TbR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。初步 我们的研究观察到哮喘患者的T细胞对Treg介导的 镇压哮喘T细胞表现出增加的增殖能力和延长的存活， 这与ERK 1/2和JNK信号通路的激活增强有关。 抑制ERK 1/2而非JNK使哮喘T细胞对TcR敏感。基于 根据这些初步结果，我们推测T细胞对Treg介导的 抑制在维持慢性哮喘中的Th 2型炎症中起重要作用， ERK 1/2及其下游效应子JunB参与了这种耐药。我们将测试 这一假设有两个具体目标：1）。定义和表征T细胞抵抗 哮喘中调节性T细胞介导的抑制。2）。研究ERK 1/2信号传导的作用 途径介导T细胞抗性。在具体目标#1下，我们将检查T细胞抗性 在过敏性哮喘患者、健康人和疾病对照中，建立其临床相关性 和疾病相关性。我们还将研究细胞因子和共刺激因子的作用。 分子在建立T细胞抗性中的作用。在具体目标#2下，我们将审查 ERK 1/2信号传导模块通过诱导一种新的信号传导通路建立自我维持机制。 MEK 1依赖性正反馈环和MKP 3依赖性负反馈的抑制 循环.我们将研究ERK 1/2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，使用诱导型基因敲除和转基因 接近。该提案很重要，因为它解决了持久性的机制， 哮喘的慢性炎症T细胞对Treg介导的抑制的抗性是一种免疫抑制剂。 相对较新的观察结果，可能对慢性炎症中的持续性炎症很重要。 哮喘以外的疾病对T细胞抗性的分子理解可以帮助开发 用于治疗哮喘和其它过敏性疾病的新的治疗方式。

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.