Metabolic control of regulatory T cells during metabolic stress caused by viral pneumonia

病毒性肺炎引起代谢应激期间调节性 T 细胞的代谢控制

• 批准号: 10537166
• 负责人: Manuel Andrés Torres Acosta
• 金额: $ 4.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537166
• 关键词: 2019-nCoV; 5' -AMP-activated protein kinase; Acetyl Coenzyme A; Amphiregulin; Autoimmunity; Automobile Driving; Biogenesis; CD4 Positive T Lymphocytes; COVID-19 pandemic; Carnitine Palmitoyltransferase I; Catalytic Domain; Cell Lineage; Cell Respiration; Cell physiology; Cells; Consumption; DNA; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; DNA-dependent protein kinase; Data; Development; Engraftment; Environment; Epigenetic Process; Equipment; Exhibits; FOXP3 gene; Fatty Acids; Functional disorder; Funding; Gene Expression; Generations; Genetic Transcription; Growth; Homeostasis; Hypermethylation; Hypoxia; Immune; Immune response; Immunology; Impairment; In Vitro; Inflammatory; Influenza; Influenza A virus; Knock-out; Knockout Mice; Link; Literature; Lung; Lung diseases; Maintenance; Mediating; Mentorship; Metabolic; Metabolic Control; Metabolic stress; Metabolism; Methylation; Mitochondria; Molecular; Mus; Natural regeneration; Nutrient Depletion; Oxidative Phosphorylation; Oxidative Stress; Oxides; Pathology; Pharmacology; Process; Protein Kinase; Pulmonary Inflammation; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Research; Resolution; Role; Scientist; Stress; System; Testing; Training; Viral Pneumonia; cell type; effector T cell; epigenetic regulation; experience; experimental study; fatty acid oxidation; immune self tolerance; in vivo; influenza infection; influenza pneumonia; influenzavirus; long chain fatty acid; loss of function; lung injury; lung repair; melanoma; mortality; mouse model; new therapeutic target; overexpression; pathogen; promoter; protective effect; repaired; response; subcutaneous; tissue repair; transcription factor; tumor; tumor microenvironment

PROJECT SUMMARY Regulatory T (Treg) cells are a subset of CD4+ T cells that maintain immune self-tolerance and mediate recovery from viral pneumonia by resolving lung inflammation and orchestrating tissue repair after lung injury. Treg cells also display metabolic plasticity; they modulate which substrates they acquire and how they metabolize them to support their functions in metabolically stressful microenvironments. AMP-activated Protein Kinase (AMPK) serves as a master regulator metabolic homeostasis by inducing energy-replenishing processes during energetic stress. AMPK promotes mitochondrial biogenesis (via epigenetic induction of the mitochondrial mass-promoting molecule PGC-1α) and long-chain fatty acid oxidation (LC-FAO, via activation of the mitochondrial LC-FA importer CPT1) in states of energy depletion. Treg cells have high levels of AMPK, and pharmacologic activation of AMPK induces Treg cell generation in vitro and in mouse models of lung disease. Surprisingly, Treg cell- specific loss of AMPK in vivo does not lead to spontaneous lethal autoimmunity or other signs of Treg cell dys- function, suggesting that AMPK is redundant in Treg cells at homeostatic conditions. To explore the role of AMPK in the Treg cell response to pathologies associated with metabolic stress (nutrient depletion, hypoxia, and oxidative stress), we bred Treg cell-specific AMPK knockout (Treg AMPK KO) mice and challenged them with either intratracheal instillation of influenza virus or subcutaneous engraftment of B16 melanoma tumors. While influenza virus-inoculated Treg AMPK KO mice had lower survival, tumors of Treg AMPK KO mice exhibited impaired growth and smaller volumes relative to controls. These results suggest that AMPK-deficient Treg cells undergo loss-of-function in settings of pathology-induced metabolic stress. Therefore, we hypothesize that Treg cell AMPK-mediated induction of mitochondrial mass and LC-FA oxidation are required for their pro-recovery function during influenza pneumonia. To elucidate the causal mechanisms through which AMPK promotes Treg cell pro-recovery function in the injured lung, we will leverage mice with Treg cell-specific deficiency of either AMPK and CPT1, along with influenza virus infection as a murine model of viral pneumonia. Our Specific Aims are to determine 1) whether AMPK promotes Treg cell pro-recovery function following influenza pneumonia by creating a permissive DNA hypomethylation landscape at Ppargc1a (encodes PGC-1α) to sustain their mitochondrial mass, and 2) whether AMPK-dependent mitochondrial import of LC-FAs is required for Treg cell pro-recovery function following influenza pneumonia. The PI's excellent mentorship network consists of experienced scientists in the fields of immunology, epigenetics, metabolism, and lung disease, all of whom will provide both day-to-day and high-level support during the funding period. The PI's environment is outstanding, with all necessary facilities, equipment, and expertise to complete the research strategy and training plan.

项目概要 调节性 T (Treg) 细胞是 CD4+ T 细胞的一个子集，可维持免疫自我耐受并介导恢复 通过解决肺部炎症和协调肺损伤后的组织修复来预防病毒性肺炎。 还表现出代谢可塑性；它们调节它们获得的底物以及它们如何代谢它们 支持其在代谢应激微环境中的功能。 通过在精力充沛期间诱导能量补充过程，充当代谢稳态的主要调节剂 AMPK 促进线粒体生物合成（通过线粒体质量促进的表观遗传诱导）。 分子 PGC-1α）和长链脂肪酸氧化（LC-FAO，通过激活线粒体 LC-FA 能量消耗状态下的输入细胞 CPT1) 具有高水平的 AMPK 和药理活性。 AMPK 在体外和小鼠肺部疾病模型中诱导 Treg 细胞生成。 体内 AMPK 的特异性缺失不会导致自发性致死性自身免疫或 Treg 细胞失调的其他迹象。 功能，表明 AMPK 在稳态条件下的 Treg 细胞中是多余的。 探讨 AMPK 的作用。 Treg 细胞对代谢应激相关病理的反应（营养耗尽、缺氧和 氧化应激），我们培育了 Treg 细胞特异性 AMPK 敲除（Treg AMPK KO）小鼠，并用 气管内滴注流感病毒或皮下植入 B16 黑色素瘤肿瘤。 接种流感病毒的 Treg AMPK KO 小鼠存活率较低，Treg AMPK KO 小鼠的肿瘤表现出 与对照相比，生长受损且体积较小。这些结果表明 AMPK 缺陷的 Treg 细胞。 在病理引起的代谢应激的情况下经历功能丧失。 细胞 AMPK 介导的线粒体质量诱导和 LC-FA 氧化是其促进恢复所必需的 阐明 AMPK 促进 Treg 的因果机制。 细胞在受伤的肺中促进恢复功能，我们将利用具有 Treg 细胞特异性缺陷的小鼠 AMPK 和 CPT1 以及流感病毒感染作为病毒性肺炎的小鼠模型。 确定 1) AMPK 是否促进流感肺炎后 Treg 细胞的促恢复功能 在 Ppargc1a（编码 PGC-1α）处创建一个允许的 DNA 低甲基化景观，以维持其 线粒体质量，2) Treg 细胞是否需要 AMPK 依赖性线粒体导入 LC-FA 流感肺炎后的促进康复功能 PI 的优秀指导网络包括： 免疫学、表观遗传学、代谢和肺部疾病领域经验丰富的科学家，他们都将 在资助期间提供日常和高层支持 PI的环境非常出色， 拥有完成研究策略和培训计划所需的所有设施、设备和专业知识。