代谢调控T细胞分化的分子机制及其应用

Effector T cell differentiation is accompanied by dramatic changes of nutrient utilization and metabolic pathways, but the causal role of these changes and the underlying mechanism remain largely unknown. A metabolic hallmark of activated T cell is aerobic glycolysis (the Warburg Effect), which refers to the conversion of glucose to lactate in the presence of oxygen. Aerobic glycolysis was initially described in tumor cells by Otto Warburg in 1920s, and numerous studies have investigated this phenomenon in vitro, but the physiological roles of aerobic glycolysis is still controversial. By converting pyruvate to lactate, lactate dehydrogenase A (LDHA) determines the chemical reaction of aerobic glycolysis, therefore is the key to decipher the secret of aerobic glycolysis. Using a mouse model with T cell-specific ablation of Ldha, we investigated the role of LDHA-mediated aerobic glycolysis in T cell biology. Contrary to expectation, we surprisingly found that aerobic glycolysis is dispensable for the development and homeostasis of T cell, which argues against an essential role of aerobic glycolysis in cell growth and proliferation under homeostatic condition. Instead, we discovered that aerobic glycolysis plays a unique role in T helper cell differentiation. TH1 cell differentiation is impaired in the absence of LDHA, which protects mice from lethal inflammatory diseases. Mechanistically, aerobic glycolysis is critical for maintaining the level of acetyl-CoA, a central metabolite in carbon metabolism, which promotes histone acetylation and transcription of key cytokines involved in effector function of T cell including IFN-g. This study uncovered a critical role and the underlying mechanism of aerobic glycolysis in TH1 cell differentiation, and paved the way for treating inflammatory disease by targeting T cell metabolism and epigenetics, which has been patented. This study was published in Science, and highlighted in Science, Cell Metabolism and Developmental cell, and listed as “highly cited paper” in the field. With this study as a starting point, we will continue to explore the role of metabolism in effector T cell differentiation with three aims. Aim 1: The role of aerobic glycolysis in TH17 cell differentiation and TH17-related disease; Aim 2: The role of acetyl-CoA generating enzyme ATP-citrate lyase (ACL) in effector T cell differentiation; Aim 3: Targeting LDHA and ACL to treat autoimmune disease in mouse models

T淋巴细胞在获得性免疫应答中发挥关键作用。激活的T细胞是增殖最快的哺乳动物细胞类型之一，但T细胞如何协调各种代谢途径来满足其增殖和分化的需求尚不清楚。申请人发现有氧糖酵解通过乙酰辅酶A依赖的表观遗传学途径调控辅助性TH1细胞分化，证明了T细胞有氧糖酵解在自身免疫疾病和炎症性疾病中的核心作用。该研究为代谢调控T细胞表观遗传学领域研究提供了范例，为治疗免疫相关疾病提供了新思路和新靶点（已获得相关专利）。该成果申请人以共同第一作者身份发表于Science，得到Science、Cell Metabolism和Developmental Cell的亮点评述。申请人将以该成果为基础，继续研究代谢调节T细胞分化的分子机制，包括有氧糖酵解以及乙酰辅酶A代谢调节TH17分化的分子机制及其在TH17介导的免疫疾病中的作用，探索抑制有氧糖酵解和乙酰辅酶A代谢治疗自身免疫疾病的可能性。

T细胞反应在抵抗感染和癌症方面起着关键作用，但T细胞过度活化也会导致自身免疫和炎症性疾病。人们越来越认识到，细胞代谢在T细胞稳态、活化、增殖和分化中起着T细胞反应在抵抗感染和癌症方面起着关键作用，但T细胞过度活化也会导致自身免疫和炎症性疾病。人们越来越认识到，细胞代谢在T细胞稳态、活化、增殖和分化中起着重要作用。靶向T细胞代谢是治疗免疫相关疾病的一种新策略，但确切的靶点仍不清楚。活化的T细胞即使在有氧的情况下也能将大部分葡萄糖作为乳酸进行处理，这种现象称为有氧糖酵解（Warburg效应）。我们最近发现了有氧糖酵通过“乙酰辅酶A-表观遗传学”调控机制解促进TH1细胞分化。我们的数据表明，类似的代谢表观遗传学机制也调节TH17细胞的分化和阻断实验性自身免疫性脑脊髓炎的发生。乙酰辅酶A主要来源于哺乳动物细胞中的葡萄糖，葡萄糖以丙酮酸盐的形式进入线粒体，然后以柠檬酸盐的形式输出回细胞质，然后通过ATP柠檬酸裂解酶（ACL）转化为乙酰辅酶A。为了更直接的研究乙酰辅酶A对T细胞的调节作用，我们制备了T细胞特异性ACL缺陷的小鼠，Cd4CreAclyfl/fl小鼠。T细胞缺陷ACL对TH17细胞介导的实验性自身免疫性脑脊髓炎具有减缓和削弱作用，并表现出T细胞迁移和最终分化缺陷。我们的研究证明了乙酰辅酶A的关键性调节酶ATP柠檬酸裂解酶在TH17细胞分化和TH17细胞依赖的自身免疫疾病的重要调节作用。ACL抑制剂BMS303141在体外能有效抑制TH17细胞的分化。在体内，给予BMS303141可预防实验性自身免疫性脑脊髓炎的发生，表明抑制ACL可能是治疗自身免疫性疾病的有效方法。