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

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.

项目概要 调节性 B 细胞参与许多病理生理过程，例如促进耐受性 自身免疫和器官移植，还可以减少对癌症的免疫反应。总体而言，许多研究 表明调节性 B 细胞与调节性 T 细胞一样，在调节免疫系统中发挥着至关重要的作用 许多情况。越来越多的证据凸显了强烈的异质性以及高 调节性 B 细胞亚群的功能可塑性，挑战了独特且稳定的定义。然而，一个 调节性 B 细胞的共同功能是产生免疫调节细胞因子 IL-10。虽然意义重大 人们的注意力一直集中在定义调节性 B 细胞的多种表型上，但仍然存在一个关键问题 需要了解调节 B 细胞功能的分子触发因素。在对人类进行的实验中 血 B 细胞，我们已经获得了指向控制 B 细胞的特定分子驱动因素的初步数据。 产生 IL-10 的调节性 B 细胞的产生。其中，我们注意到转录因子c-MAF， 属于激活蛋白 1 (AP-1) 超家族的因子，已知可调节 T 中细胞因子的产生 细胞和巨噬细胞。迄今为止，c-MAF 在 B 细胞中的功能尚未见报道。我们的结果 分析表明，在人类中，c-MAF 充当产生 IL-10 的 B 细胞生成的早期调节因子 具有浆母细胞表型。此外，最近发表的一篇文章以及公开可用的基因 转录数据表明 c-Maf 可以结合小鼠 B 细胞中的 Il10 基因启动子，并且 小鼠 B 细胞亚群在浆母细胞中转录程度最高。本研究旨在使用组织 特定基因敲除小鼠模型，探索并建立体内 c-Maf 在生成中的作用 抗体分泌细胞和产生 IL-10 的浆母细胞。具体来说，我们建议使用已建立的 c-Maf- floxed 小鼠和 CD19-Cre 小鼠生成 B 细胞条件性 c-Maf 敲除小鼠以测试以下内容：1） c-Maf 在浆母细胞稳态发育和抗体分泌生成中的功能 免疫后的浆母细胞和浆细胞； 2) c-Maf 对 IL-10-生成的贡献 产生调节性 B 细胞和浆母细胞。此外，这些研究将使用沙门氏菌感染 模型来测试 c-Maf 是否有助于功能性调节 B 细胞的发育，从而减少关键的 免疫反应。拟议的研究意义重大，因为它们是第一个调查 c- Maf 在 B 细胞生物学中的应用，因为它们将有助于更好地理解分子过程 一方面调节浆母细胞和体液免疫的发育，另一方面调节 调节性 B 细胞的产生会导致免疫力增强或无效。