Heterogeneity of plasma cell states is regulated by the dynamics of IRF4 expression

浆细胞状态的异质性受 IRF4 表达动态的调节

• 批准号: 10092104
• 负责人: Roger Sciammas
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092104
• 关键词: Affect; Alleles; Antibody Response; Autoimmunity; B cell differentiation; B-Cell Development; B-Lymphocytes; Blast Cell; Cell Line; Cell Lineage; Cells; Cellular biology; Characteristics; Data; Detection; Epithelial; Event; Future; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Heavy-Chain Immunoglobulins; Heterogeneity; Heterozygote; IRF4 gene; Immunity; Immunoglobulins; Infection; Knowledge; Longevity; Membrane; Methodology; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Organelles; Outcome; PTPRC gene; Pathologic; Phenotype; Plasma Cells; Play; Post-Transcriptional Regulation; Post-Translational Regulation; Process; Proteins; Regulation; Reporter; Reverse Transcriptase Polymerase Chain Reaction; Role; Secretory Cell; Secretory Rate; Shapes; Source; Spleen; System; Testing; Therapeutic; Transcript; Up-Regulation; Variant; dosage; in vivo; mouse model; mutant; novel; novel strategies; null mutation; phenotypic biomarker; plasma cell differentiation; prevent; programs; response; secretory IgM; syndecan; tissue tropism; trait; transcription factor

PROJECT SUMMARY Protective antibody responses depend upon secreted immunoglobulin. This is regulated in a stage-specific manner upon the differentiation of B cell blasts into plasma cells (PC) and depends on the sequential upregulation of the IRF4 and Blimp-1 transcription factors. Together, they orchestrate the plasma cell gene program that includes alternative processing of the immunoglobulin transcript and the regulation of genes important for secretion of large quantities of immunoglobulin, i.e. post-transcriptional and post-translational regulation, respectively. Despite this understanding, a gap in knowledge exists in what elaborates the observed in vivo heterogeneity of PC in regards to cell longevity, proliferative rates, tissue tropism, phenotypic markers, and secretory rates. Specifically, it is not understood how this hierarchical regulatory mechanism diversifies PC states, i.e. whether other regulators are engaged or whether the dynamics of the network control distinct PC states. We have found that halving Irf4 gene copies contributes to PC heterogeneity suggesting that the dynamics of the network diversifies PC states. This proposal aims to elucidate the mechanisms whereby the dynamic of IRF4 expression controls PC outcome. Furthermore, we will employ a newly developed reporter mouse that enables simultaneous detection of cells expressing secretory and membrane Ig by two spectrally distinct fluorescent proteins. Importantly, we expect this reporter system to function as a novel and differentiation-stage-unbiased approach to study cells undergoing changes in IgH expression levels and 3'end usage. Together, understanding the molecular basis of PC phenotypic and Ig usage heterogeneity will enable future methodologies to test their relevance in diverse settings which likely vary as a function of infection or pathologic states.

项目摘要 保护性抗体应答依赖于分泌的免疫球蛋白。这在一个 在B细胞母细胞分化为浆细胞（PC）后， IRF 4和Blimp-1转录因子的顺序上调。他们一起 精心安排浆细胞基因程序，包括替代加工的浆细胞， 免疫球蛋白转录和基因的调控重要的分泌大量 免疫球蛋白，即转录后和翻译后调节，分别。尽管 这种理解，知识的差距存在于阐述体内观察到的 PC在细胞寿命、增殖率、组织嗜性、表型 标记物和分泌率。具体来说，不明白这种分级监管是如何 机制使PC状态多样化，即是否有其他监管机构参与， 网络的动态控制不同的PC状态。我们发现，将Irf 4基因拷贝减半， 有助于PC的异质性表明，网络的动态多样化PC状态。 该建议旨在阐明IRF 4表达动态变化的机制， 控制PC结果。此外，我们将采用一种新开发的报告小鼠， 能够通过两种光谱同时检测表达分泌型和膜型IG的细胞， 不同的荧光蛋白。重要的是，我们希望这个报告系统能像小说一样发挥作用。 和分化阶段无偏的方法来研究经历IgH表达变化的细胞 3、使用方法和使用方法。总之，了解PC表型和IG的分子基础 使用的异质性将使未来的方法能够在不同的环境中测试它们的相关性 其可能作为感染或病理状态的函数而变化。