Contribution of c-Maf to regulatory B cells and antibody-secreting cells

c-Maf 对调节性 B 细胞和抗体分泌细胞的贡献

• 批准号: 10216794
• 负责人: Roberta Pelanda
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-28 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216794
• 关键词: Address; Adopted; Antibodies; Antibody Formation; Antibody Response; Antigen Presentation; Antigens; Attention; Autoimmunity; B-Cell Activation; B-Cell Development; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Binding; CD19 gene; Cell Compartmentation; Cell physiology; Cells; Cellular biology; ChIP-seq; Chromosomal translocation; Data; Development; Emu species; Exhibits; Generations; Genes; Genetic Transcription; Heterogeneity; Human; Human Genetics; Humoral Immunities; IL10 gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Immunoglobulin-Secreting Cells; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Interleukin-4; Knockout Mice; Knowledge; LoxP-flanked allele; Lymphoid Tissue; Maintenance; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Multiple Myeloma; Mus; Organ; Organ Transplantation; Pathologic; Phenotype; Plasma Cells; Plasmablast; Play; Process; Production; Publications; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Salmonella infections; Serum; Side; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; base; cell transformation; cell type; chronic inflammatory disease; cytokine; experimental study; factor C; functional plasticity; hyperglobulinemia; immune system function; immunoregulation; in vivo; knock-down; macrophage; mouse model; novel; overexpression; polarized cell; prevent; promoter; transcription factor; transcriptome sequencing; Address; Adopted; Antibodies; Antibody Formation; Antibody Response; Antigen Presentation; Antigens; Attention; Autoimmunity; B-Cell Activation; B-Cell Development; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Binding; CD19 gene; Cell Compartmentation; Cell physiology; Cells; Cellular biology; ChIP-seq; Chromosomal translocation; Data; Development; Emu species; Exhibits; Generations; Genes; Genetic Transcription; Heterogeneity; Human; Human Genetics; Humoral Immunities; IL10 gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Immunoglobulin-Secreting Cells; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Interleukin-4; Knockout Mice; Knowledge; LoxP-flanked allele; Lymphoid Tissue; Maintenance; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Multiple Myeloma; Mus; Organ; Organ Transplantation; Pathologic; Phenotype; Plasma Cells; Plasmablast; Play; Process; Production; Publications; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Salmonella infections; Serum; Side; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; base; cell transformation; cell type; chronic inflammatory disease; cytokine; experimental study; factor C; functional plasticity; hyperglobulinemia; immune system function; immunoregulation; in vivo; knock-down; macrophage; mouse model; novel; overexpression; polarized cell; prevent; promoter; transcription factor; transcriptome sequencing

PROJECT SUMMARY Regulatory B cells are involved in many pathophysiological processes, such as promoting tolerance in autoimmunity and organ transplantation, but also reducing immune responses to cancer. Overall, many studies indicate that regulatory B cells, like regulatory T cells, play a crucial role in regulating the immune system in many circumstances. A growing body of evidence highlights the strong heterogeneity as well as a high functional plasticity of regulatory B-cell subsets, which challenge a unique and stable definition. However, a common function of regulatory B cells is to produce the immunoregulatory cytokine IL-10. While significant attention has been focused on defining the multiple phenotypes of regulatory B cells, there remains a critical need to understand the molecular triggers of regulatory B-cell functions. In experiments performed with human blood B cells, we have obtained preliminary data pointing to specific molecular drivers that control the generation of IL-10-producing regulatory B cells. Among them, we noticed the transcription factor c-MAF, a factor belonging to the activator protein-1 (AP-1) superfamily and known to modulate cytokine production in T cells and macrophages. To date, a function of c-MAF in B cells has not been reported. Results from our analyses suggest that in humans, c-MAF acts as an early regulator of the generation of IL-10-producing B cells with a plasmablast phenotype. In addition, a recent publication together with publicly available gene transcription data indicate that c-Maf can bind the Il10 gene promoter in murine B cells and that, among all mouse B-cell subsets, is most highly transcribed in plasmablasts. The present study aims to use a tissue- specific gene knock-out mouse model to explore and establish in vivo the role of c-Maf in the generation of antibody-secreting cells and IL-10-producing plasmablasts. Specifically, we propose to use established c-Maf- floxed mice and CD19-Cre mice to generate B-cell conditional c-Maf knock-out mice to test the following: 1) the function of c-Maf in the steady-state development of plasmablasts and the generation of antibody-secreting plasmablasts and plasma cells after immunization; and 2) the contribution of c-Maf to the generation of IL-10- producing regulatory B cells and plasmablasts. Furthermore, these studies will use a Salmonella infection model to test whether c-Maf contributes to the development of functional regulatory B cells that reduce critical immune responses. The proposed studies are significant because they are the first to investigate the role of c- Maf in B-cell biology and because they will lead to a better understanding of the molecular processes regulating, on one side, the development of plasmablasts and humoral immunity, and on the other, the generation of regulatory B cells that contribute to exacerbated or ineffective immunity.

项目摘要 调节性B细胞参与许多病理生理过程，例如促进耐受性 自身免疫性和器官移植，但也减少了对癌症的免疫反应。总体而言，许多研究 表明调节B细胞（如调节T细胞）在调节免疫系统中起着至关重要的作用 许多情况。越来越多的证据突出了强大的异质性和高度 调节性B细胞子集的功能可塑性，这挑战了独特且稳定的定义。但是， 调节B细胞的常见功能是产生免疫调节细胞因子IL-10。虽然很重要 注意力集中在定义调节B细胞的多种表型上，仍然存在关键 需要了解调节B细胞函数的分子触发器。在人类进行的实验中 血液B细胞，我们获得了指向控制特定分子驱动因素的初步数据 生成IL-10产生的调节B细胞。其中，我们注意到转录因子C-MAF，一个 属于激活剂蛋白-1（AP-1）超家族的因子，已知可以调节T中的细胞因子的产生 细胞和巨噬细胞。迄今为止，尚未报道C-MAF在B细胞中的功能。我们的结果 分析表明，在人类中，C-MAF充当产生IL-10的B细胞的早期调节剂 具有浆膜表型。此外，最近的出版物以及公开可用的基因 转录数据表明C-MAF可以结合鼠B细胞中的IL10基因启动子，并且 小鼠B细胞亚群，最高度转录在浆膜中。本研究旨在使用组织 特定的基因敲除小鼠模型以探索和建立体内C-MAF在生成中的作用 分泌抗体细胞和产生IL-10的浆膜。具体而言，我们建议使用已建立的C-MAF- floxed小鼠和CD19-CRE小鼠生成B细胞有条件的C-MAF敲除小鼠以测试以下几点：1） C-MAF在浆膜的稳态发展中的功能和分泌抗体的产生 免疫后的浆膜和浆细胞； 2）C-MAF对IL-10-产生的贡献 产生调节性B细胞和浆膜。此外，这些研究将使用沙门氏菌感染 测试C-MAF是否有助于减少关键的功能调节B细胞的发展 免疫反应。拟议的研究很重要，因为它们是第一个研究C-的作用的人 MAF在B细胞生物学中，因为它们将导致对分子过程的更好理解 在一侧调节血浆和体液免疫的发展，另一方面是 产生导致恶化或无效免疫力的调节B细胞。