Transcriptional and metabolic regulation of Treg cell specification for the control of allergic airway disease

项目摘要 获得TH 2抑制程序使Treg细胞功能在预防过敏性疾病的发展中特异化 与哮喘相关的气道炎症。气道过敏反应出现时，有无效的 对正常无害的环境抗原的耐受性的发展和促变应性TH 2的活化 应答Foxp 3与其他转录因子的合作对于建立这种特异性至关重要 功能除了转录调控，细胞代谢的重编程是一个重要的 Treg细胞稳态和功能的调节机制。然而，Treg是如何 细胞协调免疫信号传导和细胞代谢与Treg细胞功能特化， 过敏性气道疾病（AAD）。我们最近证明，肝激酶B1（LKB 1），一个重要的调节因子， 细胞代谢，是Treg细胞在抑制过敏性气道炎症中不可或缺的。在我们的初步调查中 研究中，我们发现LKB 1的缺失导致Treg细胞中BATF的表达和IRF 4的功能受损。 通过产生具有Treg特异性消融BATF的新小鼠模型，我们揭示了BATF缺陷的Treg 细胞选择性地丧失了它们抑制TH 2介导的肺部炎症的能力。此外，我们观察到， 肺驻留Treg细胞显示出比脾Treg细胞更高水平的细胞三酰甘油（TAG）， 小鼠肺部炎症。Treg细胞中LKB 1和BATF的缺失增强了不饱和脂肪酸的生物合成 酸（UFA）和TAG，两者都与SCD 1和DGAT 2的表达增加有关， 分别用于合成UFA和TAG的酶。最后，抑制SCD 1和DGAT 2降低了 细胞脂质和随之增加的Foxp 3表达。我们假设LKB 1信号通路 用Treg细胞激活BATF/IRF 4依赖性转录组并调节乌法和TAG生物合成 控制过敏性气道疾病的功能规范。具体来说，我们将在两个方面检验这一假设。 具体目的：（1）确定LKB 1-BATF/IRF 4轴如何协调Treg中的TH 2抑制因子程序 （2）确定乌法和TAG生物合成的调节是否改变 Treg细胞在预防AAD中的作用。这项应用的研究可能会促进我们对Treg如何 细胞协调转录激活和脂质生物合成的调节，协调TH 2抑制因子 计划和显示治疗AAD的治疗机会。

PROJECT SUMMARY Acquisition of the TH2 suppressor program specializes Treg cell function in preventing the development of allergic airway inflammation associated with asthma. Airway allergic responses arise when there is ineffective development of tolerance to normally harmless environmental antigens and activation of pro-allergic TH2 responses. Cooperation of Foxp3 with additional transcription factors is crucial for establishing this specific function. Aside from the transcriptional regulation, reprogramming of cellular metabolism represents an important regulatory mechanism underlying Treg cell homeostasis and function. However, it remains elusive how Treg cells coordinate immune signaling and cellular metabolism with Treg cell functional specification in the control of allergic airway disease (AAD). We recently demonstrated that liver kinase B1 (LKB1), an important regulator of cellular metabolism, is indispensable for Treg cells in suppressing allergic airway inflammation. In our preliminary studies, we found that loss of LKB1 resulted in impaired expression of BATF and function of IRF4 in Treg cells. By generating a new mouse model with Treg-specific ablation of BATF, we revealed that BATF-deficient Treg cells selectively lost their capabilities of restraining TH2-mediated lung inflammation. Moreover, we observed that lung-resident Treg cells displayed higher levels of cellular triacylglycerols (TAGs) than splenic Treg cells from mice with lung inflammation. Loss of LKB1 and BATF in Treg cells enhanced biosynthesis of unsaturated fatty acids (UFAs) and TAGs, both associated with increased expression of SCD1 and DGAT2, the rate-limiting enzymes for synthesis of UFAs and TAGs, respectively. Finally, suppressing SCD1 and DGAT2 reduced levels of cellular lipids and concomitantly increased Foxp3 expression. We hypothesize that LKB1 signaling links activation of a BATF/IRF4-dependent transcriptome and regulation of UFA and TAG biosynthesis with Treg cell functional specification for the control of allergic airway disease. Specifically, we will test this hypothesis in two specific Aims: (1) Determine how the LKB1-BATF/IRF4 axis orchestrates the TH2 suppressor program in Treg cells for the control of allergic airway disease; (2) Determine if regulation of UFA and TAG biosynthesis alters Treg cell function in preventing AAD. Studies from this application may advance our understanding of how Treg cells coordinate transcriptional activation and regulation of lipid biosynthesis in orchestrating the TH2 suppressor program and manifest therapeutic opportunities for treating AAD.