T cell metabolism as a determinant of differentiation in allergic asthma

T 细胞代谢作为过敏性哮喘分化的决定因素

• 批准号: 8448682
• 负责人: Jeffrey C. Rathmell
• 金额: $ 36.89万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-08 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448682
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Alternative Therapies; Anabolism; Asthma; Biochemical; CD4 Positive T Lymphocytes; Cell Respiration; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Data; Disease; ERR1 protein; Equilibrium; Eragrostis; Extrinsic asthma; Frequencies; Generations; Glucocorticoid Receptor; Glucose; Glutamine; Immunity; Individual; Inflammation; Inflammatory; Lipids; Lung; Lung diseases; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Modeling; Mus; Nuclear Hormone Receptors; Pathway interactions; Pattern; Play; Population; Protein Kinase; Pyruvate; Regulation; Regulatory T-Lymphocyte; Rest; Role; Supporting Cell; T cell differentiation; T cell regulation; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; United States; airway remodeling; allergic response; cell type; glucose metabolism; in vivo; interest; metabolomics; novel; novel strategies; oxidation; prevent; programs; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the lung that results in airway remodeling and acute pulmonary allergic responses that can be debilitating or fatal. Many individuals with severe asthma do not respond or are poorly responsive to current therapies and alternative methods to treat or manage this disease are essential. One approach that may allow specific control over immunity in asthma is to influence differentiation pathways of mature CD4 T cells into effector (Teff) or inducible regulatory (Treg) subsets. Asthma has been associated with an imbalance of these subsets marked by increased frequency of Teff and decreased Treg cells, yet mechanisms that control this balance are poorly understood. We propose that modulation of T cell metabolism may provide a new approach to manipulate CD4 T cell differentiation and treat asthma. We have shown that T cell stimulation promotes a switch from an oxidative to a predominantly glycolytic metabolism in which glucose-derived pyruvate is converted to lactate or used to support biosynthesis rather than mitochondrial oxidation. Cell metabolism must, however, be tuned to specific cellular demands and consistent with the distinct roles and activities of Teff and Treg CD4 T cells, we found that differentiated CD4 T cell subsets had distinctly different metabolic patterns and requirements. Specifically, Teff cells were highly glycolytic and required glucose for metabolism and survival while Treg cells remained oxidative and required lipids for mitochondrial oxidation. Further, we found that the nuclear hormone receptor Estrogen Related Receptor-alpha (ERRa) was activated following T cell stimulation and essential to promote increased glucose metabolism of Teff. Importantly, inhibition of ERRa selectively suppressed Teff generation whereas treatment of mice with activators of AMP-protein kinase (AMPK) to directly promote oxidative metabolism increased Treg generation in vivo. Together these findings have led to the hypothesis that T cell metabolism is a critical factor in T cell differentiation into effector or regulatory populations with glycolytic metabolism favoring inflammatory effector and oxidative metabolism favoring regulatory T cells and that manipulation of T cell metabolism through ERRa and AMPK may allow for selective Treg generation to suppress allergic asthma. To test this hypothesis we propose to: (1) Determine how metabolism influences CD4 T cell differentiation into Treg or Teff populations; (2) Examine the role of ERRa in regulation of T cell metabolism and differentiation; and (3) Establish how modulation of T cell metabolism in vivo impacts a model of allergic asthma. Together these aims will define the regulation and role of Teff and Treg metabolic programs and point towards metabolic regulatory mechanisms that can be targeted in novel therapies to treat or control asthma.

描述（由申请人提供）：哮喘是一种慢性肺部炎症性疾病，可导致气道重塑和急性肺部过敏反应，这些反应可能使人衰弱或致命。许多患有严重哮喘的个体对当前疗法没有反应或反应不良，治疗或管理这种疾病的替代方法至关重要。一种可能允许特异性控制哮喘免疫的方法是影响成熟CD 4 T细胞分化为效应子（Teff）或诱导调节（Treg）亚群的分化途径。哮喘与这些亚群的不平衡有关，其特征是Teff频率增加和Treg细胞减少，但控制这种平衡的机制知之甚少。我们认为，调节T细胞代谢可能提供一种新的方法来操纵CD 4 T细胞分化和治疗哮喘。我们已经表明，T细胞刺激促进从氧化代谢到主要糖酵解代谢的转变，其中葡萄糖衍生的丙酮酸转化为乳酸或用于支持生物合成而不是线粒体氧化。然而，细胞代谢必须根据特定的细胞需求进行调整，并与Teff和Treg CD 4 T细胞的不同作用和活性一致，我们发现分化的CD 4 T细胞亚群具有明显不同的代谢模式和需求。具体地，Teff细胞是高度糖酵解的，并且需要葡萄糖用于代谢和存活，而Treg细胞保持氧化并且需要脂质用于线粒体氧化。此外，我们发现核激素受体雌激素相关受体-α（ERRa）在T细胞刺激后被激活，并且对于促进Teff的葡萄糖代谢增加是必需的。重要的是，ERRa的抑制选择性地抑制Teff生成，而用AMP-蛋白激酶（AMPK）的活化剂处理小鼠以直接促进氧化代谢增加体内Treg生成。这些发现共同导致了以下假设：T细胞代谢是T细胞分化为效应或调节群体的关键因素，其中糖酵解代谢有利于炎症效应细胞，氧化代谢有利于调节T细胞，并且通过ERRa和AMPK操纵T细胞代谢可以允许选择性Treg生成以抑制过敏性哮喘。为了验证这一假设，我们提出：（1）确定代谢如何影响CD 4 T细胞分化为Treg或Teff群体;（2）检查ERRa在调节T细胞代谢和分化中的作用;和（3）确定体内T细胞代谢的调节如何影响过敏性哮喘模型。这些目标将共同定义Teff和Treg代谢程序的调节和作用，并指向可以在治疗或控制哮喘的新疗法中靶向的代谢调节机制。