T cell metabolism as a determinant of differentiation in allergic asthma

描述(申请人提供)：哮喘是一种慢性肺部炎症性疾病，导致呼吸道重塑和急性肺过敏反应，可使人虚弱或致命。许多严重哮喘患者对目前的治疗方法没有反应或反应不佳，治疗或管理这种疾病的替代方法是必不可少的。一种可能允许对哮喘免疫进行特异性控制的方法是影响成熟的CD4T细胞分化为效应者(TEFF)或诱导性调节(Treg)亚群的途径。哮喘与这些亚群的失衡有关，表现为TJeff频率增加和Treg细胞减少，但控制这种平衡的机制尚不清楚。我们认为，T细胞代谢的调节可能为调控CD4T细胞分化和治疗哮喘提供新的途径。我们已经证明，T细胞刺激促进了从氧化到以糖酵解为主的代谢的转换，在这种代谢中，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TJeff和Treg两种CD4T细胞的不同作用和活性相一致，我们发现分化的CD4T细胞亚群具有明显不同的代谢模式和要求。具体地说，TJeff细胞高度糖酵解，需要葡萄糖来新陈代谢和生存，而Treg细胞保持氧化状态，需要脂质来进行线粒体氧化。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T细胞糖代谢的增加是必不可少的。重要的是，抑制ERRA选择性地抑制TJeff的产生，而用AMP-蛋白激酶激活剂(AMPK)直接促进体内氧化代谢的小鼠增加了Treg的产生。综上所述，这些发现导致假设T细胞代谢是T细胞分化为效应者或调节性群体的关键因素，糖酵解代谢有利于炎症效应者，氧化代谢有利于调节性T细胞，并且通过ERRA和AMPK操纵T细胞代谢可能允许选择性Treg产生以抑制过敏性哮喘。为了验证这一假设，我们建议：(1)确定代谢如何影响CD4T细胞分化为Treg或Teff群；(2)检查Erra在调节T细胞代谢和分化中的作用；以及(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TJeff和Treg代谢计划的调节和作用，并指向可作为治疗或控制哮喘的新疗法的靶点的代谢调节机制。

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.