Foxp3+ regulatory T cell-dependent treatment of allergic inflammation by glucocorticoids

摘要 哮喘是一种慢性气道炎症性疾病，影响超过 2500 万美国人。每年一度的 哮喘造成的经济损失超过 500 亿美元，使哮喘成为最常见和最昂贵的疾病之一 疾病。过敏原特异性 Th2 型 CD4 T 细胞激活和嗜酸性粒细胞浸润是哮喘的标志 炎症。口服或吸入糖皮质激素已成为有效控制哮喘的一线治疗方法 50多年来。然而，糖皮质激素介导的治疗的确切机制尚不清楚 明白了。此外，一群哮喘患者出现了类固醇抵抗性哮喘。与传统的不同 嗜酸性粒细胞为主的 Th2 型炎症、类固醇抵抗性哮喘炎症与 显示 Th17 类型特征的效应 CD4 T 细胞的中性粒细胞浸润。当前应用程序已构建 意外观察到合成糖皮质激素地塞米松未能抑制嗜酸性粒细胞气道 Foxp3 Tregs 缺失时的炎症，Foxp3 Tregs 是一种 CD4 T 细胞亚群，在调节中发挥核心作用 免疫力和耐受性。过继性 Treg 转移到这种情况下可以恢复地塞米松的治疗效果， 支持 Tregs 的作用。我们还发现中性粒细胞性气道炎症模型即地塞米松 使用地塞米松联合 IL-27（Treg 必需的细胞因子）治疗后，耐药性减弱 抑制功能。地塞米松/IL-27介导的中性粒细胞炎症治疗也失败了 Treg 缺失或 Treg 特异性 Il27ra-/- 小鼠，表明 Tregs 和 IL-27 信号在 Tregs 中发挥关键作用。 这些初步结果使我们提出 Dex 信号传导诱导 Treg 抑制功能，从而 限制嗜酸性粒细胞炎症反应，而 Dex 控制中性粒细胞炎症反应 需要 IL-27 向 Tregs 传递额外的信号。提出了三个具体目标来测试 假设。目标 1 是检验 Dex 通过以下方式下调嗜酸性粒细胞性气道炎症的假设： 针对 Tregs。目标 2 是检验中性粒细胞炎症破坏 Dex 诱导的 Treg 的假设 控制气道炎症，导致 Dex 耐药。目标 3 是检验 IL-27 信号传导的假设 改善 Tregs 中的 Dex 反应性，抑制 Dex 耐药性中性粒细胞炎症。完成 拟议的研究将揭示 Tregs 调节 GC 的先前未知机制 易感和GC耐药的过敏性气道炎症，为开发新型药物开辟了新的机会 通过针对 Tregs 来提高 GC 治疗效果并克服 GC 耐药性的方法。

Abstract Asthma is a chronic inflammatory disease of the airways, affecting >25 million Americans. The annual economic cost for asthma exceeds 50 billion dollars, making asthma one of the most common and costly disease. Allergen specific Th2 type CD4 T cell activation and eosinophil infiltration are hallmarks of asthmatic inflammation. Oral or inhaled glucocorticoids have been the frontline treatment to effectively manage asthma for more than 50 years. Yet, the precise mechanisms underlying glucocorticoid-mediated treatment are not well understood. In addition, a cohort of asthmatic patients develops steroid-resistant asthma. Unlike conventional eosinophil-dominant Th2 type inflammation, steroid-resistant asthmatic inflammation is associated with neutrophilic infiltration with effector CD4 T cells displaying Th17 type signature. The current application is built upon unexpected observations that synthetic glucocorticoid, dexamethasone, fails to inhibit eosinophilic airway inflammation in the absence of Foxp3+ Tregs, a CD4 T cell subset that plays a central role in regulating immunity and tolerance. Adoptive Treg transfer into this condition restores dexamethasone treatment effects, supporting the role of Tregs. We also found that neutrophilic airway inflammation model that is dexamethasone resistant is attenuated upon treating with dexamethasone combined with IL-27, a cytokine essential for Treg suppressive functions. Dexamethasone/IL-27-mediated treatment of neutrophilic inflammation also failed in Treg-depleted or in Treg-specific Il27ra-/- mice, suggesting key roles of Tregs and of IL-27 signaling in Tregs. These preliminary results have led us to propose that Dex signaling induces Treg suppressive functions that limit eosinophilic inflammatory responses whereas control of neutrophilic inflammatory responses by Dex requires additional signals conferred by IL-27 to the Tregs. Three specific aims are proposed to test the hypothesis. Aim 1 is to test the hypothesis that that Dex downregulates eosinophilic airway inflammation by targeting Tregs. Aim 2 is to test the hypothesis that neutrophilic inflammation subverts Dex-induced Treg control of airway inflammation, resulting in Dex resistance. Aim 3 is to test the hypothesis that IL-27 signaling improves Dex responsiveness in Tregs to inhibit Dex-resistant neutrophilic inflammation. Completing the proposed studies will uncover the previously unknown mechanisms by which Tregs regulate both GC susceptible and GC resistant allergic airway inflammation, opening new opportunities to develop novel approaches to improve GC’s therapeutic efficacy and to overcome GC resistance by targeting Tregs.