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Diet-derived oxysterols shape intestinal B cell fate by controlling intracellular cholesterol metabolism

饮食来源的氧甾醇通过控制细胞内胆固醇代谢来塑造肠道 B 细胞的命运

基本信息

批准号：
10626049
负责人：
Andrea Reboldi
金额：
$ 46.72万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-25 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626049
关键词：
16S ribosomal RNA sequencing 25-hydroxycholesterol Adaptive Immune System Antibiotics Antibodies Antibody Formation Antibody Response Antigens Area B Cell Proliferation B cell differentiation B-Cell Activation B-Lymphocytes Bacterial Antigens Bile Acids Binding Proteins Biological Assay Biological Availability Biological Process Cell Fate Control Cells Cholesterol Cholesterol Homeostasis Clone Cells Communities Complex Couples Cues Data Diet Dietary Cholesterol Dietary Intervention Environment Exposure to Follicular Dendritic Cells Foundations Gastrointestinal tract structure Gene Expression Profile Generations Genes Genetic Transcription Helper-Inducer T-Lymphocyte Homeostasis Immune Immune system Immunology Impairment Individual Intervention Intestines Lead Link Lipids Maintenance Maps Mediating Memory B-Lymphocyte Metabolic Metabolism Microanatomy Modeling Molecular Mus Nature Output Pathway interactions Peripheral Phenocopy Plasma Cells Play Process Production Reaction Reagent Regulation Response Elements Role Shapes Source Spleen Sterols Stimulus Stromal Cells Structure of germinal center of lymph node Testing Transcriptional Regulation Work adaptive immunity cholesterol absorption commensal bacteria dietary dietary manipulation draining lymph node expectation in vivo insight intestinal homeostasis lipid biosynthesis lipid metabolism liquid chromatography mass spectrometry lymph nodes machine learning method microbial microbiome microorganism antigen novel oxysterol binding protein pharmacologic plasma cell differentiation prevent response transcription factor transcriptome sequencing

项目摘要

Abstract B lymphocytes in the gastrointestinal tract are constantly stimulated by commensals microbial antigens. In order to prevent commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep process of B cell proliferation and selection in the germinal center, which eventually gives rise to either antibody secreting plasma cells or memory B cells. Intestinal B cells are also exposed to dietary and microbial metabolites during their activation and differentiation, but how these environmental cues shape B cell fate and antibody response in the gut is poorly understood. Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of individual B cell clones in the gut remains a central question in immunology. Several lines of evidence indicate that metabolic switches act as intrinsic regulators of germinal center B cell response. However, how B cells integrate metabolite sensing with germinal center and antibody response remains undefined to date. In this application we test the hypothesis that the oxysterol 25-HC, an oxidized form of cholesterol, directly controls germinal center B cell response through its interaction with the Sterol Response Element Binding Protein 2 (SREBP2). SREBP2 is a key regulator of intracellular cholesterol homeostasis, and its transcriptional activity in the intestinal germinal center B cells couples lipid metabolism and B cell differentiation in the intestine. We also hypothesize that follicular dendritic cells (FDCs), stromal cells which are located in the germinal center, produce 25-HC in response to dietary cholesterol and microbiome, therefore linking rapidly changing intestinal homeostasis to B cell fate. Accumulating evidence indicates that 25-HC controls SREBP2 processing, but the implication for this cross talk in B cells in the gut has not been investigated so far. Our aims are: 1) To test the hypothesis that SREBP2 activity controls germinal center B cell transcriptional profile and B cell fate; and 2) To define the environmental and cellular cues that regulate 25-HC niche. The proposed studies examine a very poorly understood crosstalk between oxidized form of cholesterol, intestinal metabolism and adaptive immune system activation. It is our expectation that these studies will increase our understanding of how intestinal metabolism shapes B cell responses and adaptive immunity. Furthermore, these studies will provide a foundation for better understanding of the relationship between lipid metabolism and differentiation in immune cells.

摘要