Role of glutamine metabolism in Dendritic Cell Development

项目摘要 传统的树突状细胞(CDC)通过连接先天免疫和获得性免疫在保护性免疫中发挥重要作用 免疫反应。疾控中心可以区分“自我”和“非自我”(例如病原体)或“改变的自我”(例如 癌症)通过专门的模式识别受体，并帮助协调适当的适应性免疫 回应。CDC1和CDC2是CDC的两个主要子集，CDC1具有独特的交叉能力。 提出对病毒和癌症免疫至关重要的抗原。疾病预防控制中心的循环前体(前 CDC)侵入组织，分化为CDC1和CDC2。这些疾病预防控制中心的相对分布 不同的组织类型和病理条件下的亚群不同，提示组织的作用 CDC前分化的微环境。组织微环境中的哪些因素可能对此进行调节 然而，人们对这一过程仍知之甚少。我们的初步研究表明，CDC1分化是 受氨基酸谷氨酰胺代谢转化为谷氨酸的局部可获得性调节。 在快速增殖的细胞或分解代谢应激期间，谷氨酰胺的摄取和利用显著增加， 有可能造成谷氨酰胺缺乏的局部微环境。因此，我们假设新陈代谢 组织中的适应通过调节谷氨酰胺水平改变局部CDC1的分化。在这项提案中，我们寻求 了解CDC1分化的哪些步骤受谷氨酸及其基础分子的调控 机制。我们将专注于基因表达的表观遗传调控和潜在的氧化应激 谷氨酸调节这一效应的途径。来自拟议工作的发现可能会打开新的 将组织代谢适应与其免疫微环境联系起来的一系列研究。

Project Summary Conventional dendritic cells (CDC) play a central role in protective immunity by connecting innate and adaptive immune responses. CDCs can distinguish `self' from `non-self' (example pathogen) or `altered-self' (example cancer) through specialized pattern recognition receptors and help orchestrate the appropriate adaptive immune response. CDC1 and CDC2 are the two major subsets of CDCs with CDC1s having the unique capacity to cross- present antigens that is critical for immunity against viruses and cancer. Circulating precursors of CDCs (Pre- CDCs) infiltrate tissue where they differentiate into CDC1 and CDC2. The relative distribution of these CDC subsets differ between tissue types and under pathological conditions, suggesting a role of tissue microenvironment in Pre-CDC differentiation. What factors in the tissue microenvironment might regulate this process, however, remains poorly understood. Our preliminary studies show that CDC1 differentiation is regulated by local availability of the amino acid glutamine through its metabolic conversion into glutamate. Glutamine uptake and utilization increases significantly in rapidly proliferating cells or during catabolic stress, potentially creating a glutamine deficient local microenvironment. Hence, we hypothesize that metabolic adaptations in tissue alters local CDC1 differentiation by modulating glutamine levels. In this proposal, we seek to understand which steps of CDC1 differentiation is regulated by glutamate and its underlying molecular mechanism. We will focus on epigenetic regulation of gene expression and oxidative stress as potential pathways by which glutamate mediates this effect. Findings from the proposed work can potentially open new lines of research linking tissue metabolic adaptations to its immune microenvironment.