Metabolic programming in TH17 cell differentiation

描述(由申请人提供)：当原始T细胞在适当的共刺激和细胞因子的共同刺激下遇到外来抗原时，它们会经历快速和广泛的克隆性扩张，并分化为特定的谱系。CD4+T细胞中两个密切相关的谱系是促进炎症的TH17细胞和抑制免疫反应的Treg细胞。我们和其他人最近的工作表明，T细胞代谢途径与T细胞分化和免疫功能密切相关，这意味着通过靶向代谢过程来调节T细胞免疫反应具有巨大的潜力。我们和其他人最近的工作表明，在TH17分化期间，糖酵解是优先的，但在iTreg分化期间不是，并表明这种代谢偏好在推动细胞向TH17或iTreg方向发展的过程中发挥了作用。这些研究表明存在T细胞系特异性代谢程序和T细胞分化代谢调节的细胞内在机制。然而，T细胞系特异性代谢程序的完整轮廓、T细胞分化过程中代谢重编程的调节机制以及靶向T细胞代谢程序的潜在治疗应用仍然难以捉摸。到目前为止，我们的研究表明，转录因子Myc是协调调节TH17细胞代谢和分化的关键节点之一。因此，我们假设Myc介导的代谢重编程和代谢检查点促进了TH17的分化，并代表了自身免疫性疾病的一个新的治疗靶点。我们的目标直接来自于这一假设，我们建议应用生化、细胞和遗传学方法来研究Myc和代谢重新编程在调节T细胞分化中的作用。具体地说，我们将：a)确定Th17谱系特异性的代谢重编程、代谢成瘾和Myc在调节Th17代谢和分化中的作用(目标1)；b)阐明Myc、TORc1和Hif1�之间在调节Th17分化中的代谢检查点的动态相互作用(目标2)；以及c)评估代谢计划作为Th17介导的自身免疫性疾病的新的治疗靶点(目标3)。我们的建议使用遗传模型和代谢方法，并以TH17细胞为起点，剖析代谢途径调节如何在生理病理环境中影响免疫反应。这项研究产生的见解将揭示免疫系统中信号通路和代谢通路之间的基本相互作用。这些对免疫代谢的研究可能确定炎症性和自身免疫性疾病的新的治疗干预策略。

DESCRIPTION (provided by applicant): When naive T cells encounter foreign antigen along with proper co-stimulation and cytokines, they undergo rapid and extensive clonal expansion and differentiate into specific lineages. Two closely related lineages in CD4+ T cells are TH17 cells, which promote inflammation, and Treg, which dampen immune responses. Recent work from us and others has shown that T cell metabolic pathways are tightly and ubiquitously linked with T cell differentiation and immune functions, implicating a great potential for modulating T cell immune responses through targeting metabolic processes. Recent work from us and others indicated a preference on glycolysis during TH17 differentiation but not during iTreg differentiation, and suggests that such metabolic preferences play a role in driving cell fate towards TH17 or iTreg. These studies indicate the presence of T cell lineage- specific metabolic programs and cell intrinsic mechanisms of metabolic regulation of T cell differentiation. However, the complete profile of T cell lineage-specific metabolic programs, the regulatory mechanisms of metabolic reprogramming during T cell differentiation and the potential therapeutic application of targeting T cell metabolic programs remain elusive. Our studies to date have implicated the transcription factor Myc as one of the key "nodes" coordinately regulating TH17 cell metabolism and differentiation. We therefore hypothesize that the Myc-mediated metabolic reprogramming and metabolic checkpoint fuels TH17 differentiation and represents a novel therapeutic target of autoimmune diseases. Our goals follow directly from this hypothesis and we propose to apply biochemical, cellular and genetic approaches to investigate the role of Myc and metabolic reprogramming in regulating T cell differentiation. Specifically, we will: a) determine the TH17 lineage-specific metabolic reprogramming, metabolic addiction and the role of Myc in regulating TH17 metabolism and differentiation (aim 1); b) elucidate the dynamic interplay among Myc, TORC1 and HIF1� in mediating a metabolic checkpoint in TH17 differentiation (aim 2); and c) assess the metabolic program as a novel therapeutic target for TH17-mediated autoimmune diseases (aim 3). Our proposal employs genetic models and metabolic approaches and focuses on TH17 cells as a starting point to dissect how the metabolic pathway regulation impacts immune responses in physio-pathological settings. The insights generated from this study will reveal fundamental interplays between signaling pathways and metabolic pathways in the immune system. These studies of immune metabolism may identify novel therapeutic intervention strategies for inflammatory and autoimmune diseases.