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

项目总结 TH2抑制程序的获得使Treg细胞在预防过敏发展中具有特殊功能 与哮喘相关的呼吸道炎症。呼吸道过敏反应发生在无效时 对正常无害环境抗原的耐受性和致敏性TH2的激活 回应。Foxp3与其他转录因子的协同作用是建立这种特异性的关键 功能。除了转录调控，细胞新陈代谢的重新编程是一个重要的 Treg细胞动态平衡和功能的调节机制。然而，仍然难以捉摸特雷格是如何 细胞协调免疫信号和细胞代谢与Treg细胞功能规范控制 过敏性呼吸道疾病(AAD)。我们最近证明了肝脏激酶B1(LKB1)，一个重要的调节蛋白。 细胞代谢，是Treg细胞抑制过敏性呼吸道炎症所必需的。在我们的预赛中 研究发现，LKB1的缺失导致Treg细胞BATF的表达和IRF4的功能受损。 通过建立一个新的小鼠模型与Treg特异性消融BATF，我们揭示了BATF缺陷的Treg 细胞选择性地丧失了抑制TH2介导的肺部炎症的能力。此外，我们观察到， 肺树突状细胞的三酰甘油(TAG)水平高于脾细胞。 肺部发炎的小鼠。Treg细胞中LKB1和BATF的缺失促进不饱和脂肪的生物合成 酸(不饱和脂肪酸)和标签，两者都与SCD1和DGAT2的表达增加有关，这是限速基因 分别用于合成不饱和脂肪酸和标签的酶。最后，抑制SCD1和DGAT2降低了水平 并伴随着Foxp3表达的增加。我们假设LKB1信号链 依赖BATF/IRF4的转录组的激活及Treg细胞对不饱和脂肪酸和TAG生物合成的调节 过敏性呼吸道疾病控制功能规范。具体地说，我们将分两个阶段检验这一假设 具体目标：(1)确定LKB1-BATF/IRF4轴如何协调Treg中的TH2抑制程序 用于控制过敏性呼吸道疾病的细胞；(2)确定不饱和脂肪酸和标签生物合成的调节是否改变 Treg细胞在预防AAD中的作用。对这一应用的研究可能会增进我们对Treg如何 细胞协调TH2抑制因子的转录激活和脂质生物合成的调节 规划和明确治疗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.