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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

基本信息

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
项目类别：
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

项目摘要

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.

程序总结/文摘