FCRL1 in B cell differentiation

FCRL1 在 B 细胞分化中的作用

• 批准号: 10730705
• 负责人: Timothy James Wilson
• 金额: $ 41.17万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730705
• 关键词: Accounting; Adaptor Signaling Protein; Affinity; Antibodies; Antibody Formation; Antibody Response; Antigen Presentation; Antigen Receptors; Antigens; Apoptosis; Apoptotic; Autoimmune Diseases; B cell differentiation; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Back; Bacterial Infections; Biomedical Research; Calcium Signaling; Cell Line; Cell Surface Proteins; Cell membrane; Cells; Cellularity; Clonal Expansion; Communicable Diseases; Complex; Coupled; Darkness; Data; Defect; Differentiation and Growth; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Follicular Dendritic Cells; Gene Modified; Gene Targeting; Goals; Helper-Inducer T-Lymphocyte; Home; Immune response; Immunization; Immunize; Immunoglobulin Genes; Immunologic Memory; Immunotherapy; Impairment; Infection; Inositol; Kinetics; Knowledge; Light; MAPK3 gene; Mediating; Membrane Proteins; Memory; Microscopic; Modeling; Molecular; Mus; Pathway interactions; Peripheral; Phosphoric Monoester Hydrolases; Plasma; Plasma Cells; Plasmablast; Process; Production; Proteins; Reaction; Receptor Signaling; Recycling; Role; Sampling; Signal Induction; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Training; Transgenic Organisms; Tyrosine; Vaccination; Vaccines; Virus Diseases; adaptive immune response; adaptive immunity; antigen challenge; experimental study; graduate student; growth factor receptor-bound protein 2; improved; in vivo; lymphoid structures; migration; recruit; release of sequestered calcium ion into cytoplasm; response; transmission process; undergraduate student; vaccine development; vaccine response; vaccine trial

PROJECT SUMMARY B lymphocytes are responsible for making antibodies in response to antigens from vaccination and infection. Adaptive immunity involves activating and expanding B cells that can recognize those antigens, produce neutralizing and opsonizing antibodies, and provide immunological memory. The process by which this occurs involves a complex interplay of signals inside and outside the cell to instruct B cells when to expand, modify their antigen receptor, and differentiate into memory cells or antibody-secreting plasma cells. Much of this differentiation process occurs in a specialized lymphoid structure called the germinal center. Our study seeks to understand how B cells navigate the growth and differentiation process to optimize antibody responses. We are studying a cell surface protein, FCRL1, found on all subsets of peripheral B cells. When the B cell receptor (BCR) is engaged by antigen, FCRL1 enhances intracellular calcium signals while suppressing the activation of ERK1/2. Mice deficient in FCRL1 have impaired antibody responses and fewer germinal center B cells after immunization. We hypothesize that FCRL1 is controlling B cell signals to maximize clonal expansion prior to differentiation. Using a model antigen system and Fcrl1-/- mice, this study will track the kinetics of B cell activation and differentiation throughout the germinal center response to the production of memory and plasma cells. It will examine how FCRL1-mediated ERK inhibition alters B cell differentiation, and it will begin to uncover the signaling pathway(s) used by FCRL1 to down-modulate BCR-induced ERK1/2 activation using gene-targeted and transgenic B cell lines. This study will improve our understanding of signals that provide optimal antibody responses to infection with the long-term aim of improving the efficacy and durability of vaccines and immunotherapies.

项目总结 B淋巴细胞负责针对疫苗接种的抗原产生抗体。 和感染。获得性免疫涉及激活和扩增能够识别 这些抗原，产生中和和调理抗体，并提供免疫学 记忆。发生这种情况的过程涉及内部和外部信号的复杂相互作用 在细胞外指示B细胞何时扩增，修饰其抗原受体，并分化 转化为记忆细胞或分泌抗体的浆细胞。这种分化过程很大程度上发生在 在一种叫做生发中心的特殊淋巴结构中。我们的研究试图理解 B细胞如何引导生长和分化过程以优化抗体反应。我们 正在研究一种细胞表面蛋白FCRL1，它存在于外周B细胞的所有亚群中。当 B细胞受体(BCR)与抗原结合，FCRL1增强细胞内钙信号，而FCRL1 抑制ERK1/2的激活。FCRL1基因缺陷的小鼠抗体反应受损 免疫后生发中心B细胞减少。我们假设FCRL1正在控制 B细胞在分化前发出最大限度的克隆性扩增信号。使用模型抗原系统 和Fcrl1-/-小鼠，本研究将跟踪B细胞激活和分化的动力学 生发中心对产生记忆细胞和浆细胞的反应。它将研究如何 FCRL1介导的ERK抑制改变B细胞分化，它将开始揭示 FCRL1下调bcr诱导的ERK1/2激活的信号通路(S) 基因靶向和转基因B细胞系。这项研究将提高我们对信号的理解 提供对感染的最佳抗体反应，长期目标是改善 疫苗和免疫疗法的有效性和持久性。