Bidirectional metabolic signaling in follicular helper T cell differentiation

滤泡辅助 T 细胞分化中的双向代谢信号

• 批准号: 10687027
• 负责人: Hongbo Chi
• 金额: $ 53.63万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687027
• 关键词: Activated Lymphocyte; Affinity; Amino Acids; Antibody Affinity; Antibody Formation; Antigens; Autoimmune Diseases; B-Lymphocytes; Biological; Biology; Cell physiology; Cells; Cellular Immunity; Defect; Distal; FRAP1 gene; Feeds; GTP-Binding Proteins; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Glycolysis; Growth; Guanosine Triphosphate Phosphohydrolases; Helper-Inducer T-Lymphocyte; Heterogeneity; Homologous Gene; Humoral Immunities; Immune System Diseases; Immune signaling; Immunoglobulins; Immunologic Receptors; Invaded; Knowledge; Link; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Monomeric GTP-Binding Proteins; Mus; Nutrient; Oxidative Phosphorylation; Pathway interactions; Phenotype; Post-Translational Protein Processing; Process; Proteins; Proteomics; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; Systems Biology; T cell differentiation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Translating; Up-Regulation; amino acid metabolism; effector T cell; fatty acid biosynthesis; glucose metabolism; in vivo; innovation; insight; interest; metabolome; mitochondrial metabolism; mouse genetics; novel; pathogen; programs; receptor; response; screening; single-cell RNA sequencing; transcription factor

Program Summary/Abstract Follicular helper T (Tfh) cells provide essential help for B cells and high-affinity antibody production, thereby linking cellular and humoral immunity. While much emphasis has been placed on immune receptors (e.g. ICOS) and transcription factors (e.g. Bcl6) required for Tfh differentiation, how signals are transduced from receptors to transcriptional and biological responses remains poorly defined. Emerging studies reveal nutrient signaling and metabolic reprogramming as fundamental processes underlying the growth and fate decisions of activated lymphocytes. However, many questions remain regarding the specific metabolic pathways important for T cell fate decisions (rather than as a consequence of changes in cellular phenotypes), and how immune signals intersect with nutrient inputs and metabolic programs. For instance, compared with our knowledge on glycolytic or Warburg metabolism, the function and regulation of mitochondrial metabolism are much less clear. We establish that mTOR acts as a key driver of Tfh differentiation by coordinating T cell receptor and ICOS signaling and glucose metabolism. Through unbiased screens, mouse genetic models and systems biology approaches in our preliminary studies, we also revealed crucial roles of nutrient signaling and mitochondrial metabolism in Tfh responses. Our central hypothesis is that the interplay between mTORC1 and nutrient signaling pathways and mitochondrial metabolic programs orchestrates bidirectional metabolic signaling and Tfh differentiation. Specifically, we will (1) identify the mechanisms that integrate nutrient and immune signals in Tfh responses, and (2) establish mitochondrial function and metabolic heterogeneity in Tfh responses. Importantly, despite the emerging interest in immunometabolism, how nutrient signaling and mitochondrial metabolism contribute to T cell function remains poorly understood. Building upon our expertise and innovation that combine genetic and systems biology approaches, we will address fundamental questions of immunometabolism and Tfh biology. Insights gained from this application may significantly impact our understanding of Tfh biology and manifest legitimate therapeutic opportunities.

项目概要/摘要 滤泡辅助性T（Tfh）细胞为B细胞和高亲和力抗体产生提供必要的帮助，从而 连接细胞免疫和体液免疫虽然已经将很多重点放在免疫受体（例如， ICOS）和转录因子（例如Bcl 6），信号如何从Tfh分化所需的细胞中转导， 转录和生物学反应的受体仍然不清楚。新兴研究揭示营养素 信号传导和代谢重编程作为基础的生长和命运决定的基本过程， 活化淋巴细胞然而，许多问题仍然关于特定的代谢途径重要 对于T细胞的命运决定（而不是作为细胞表型变化的结果），以及免疫 信号与营养输入和代谢程序相交。例如，与我们对 糖酵解或瓦尔堡代谢，线粒体代谢的功能和调节是不太清楚。 我们确定mTOR通过协调T细胞受体和ICOS作为Tfh分化的关键驱动因素 信号传导和葡萄糖代谢。通过无偏筛选、小鼠遗传模型和系统生物学 在我们的初步研究中，我们还揭示了营养信号和线粒体的关键作用。 Tfh反应中的代谢。我们的中心假设是mTORC 1和营养素之间的相互作用 信号通路和线粒体代谢程序协调双向代谢 信号传导和Tfh分化。具体来说，我们将（1）确定整合营养和 Tfh应答中的免疫信号，以及（2）建立Tfh中的线粒体功能和代谢异质性 应答重要的是，尽管对免疫代谢的兴趣正在兴起，但营养信号和 线粒体代谢对T细胞功能的贡献仍然知之甚少。基于我们的专业知识 和创新，结合联合收割机遗传和系统生物学的方法，我们将解决基本问题， 免疫代谢和转铁蛋白生物学。从该应用程序中获得的见解可能会对我们的 了解Tfh生物学和表现出合法的治疗机会。