Defining the role of T-bet in systemic IgA

定义 T-bet 在全身性 IgA 中的作用

• 批准号: 10751750
• 负责人: Victoria E Zoccoli-Rodriguez
• 金额: $ 4.77万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10751750
• 关键词: Address; Antibodies; B-Lymphocytes; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Chimera organism; Data; Frequencies; Gene Expression; Gene Expression Profile; Generations; Goals; Helper-Inducer T-Lymphocyte; IFNGR1 gene; Immune response; Immunity; Immunoglobulin A; Immunoglobulin Class Switching; Inflammatory; Interferon Type II; Link; Measures; Modeling; Mucous Membrane; Mus; Peyer' s Patches; Plasma; Plasma Cells; Play; Population; Proteobacteria; Reaction; Recombinant Interferon; Role; Sepsis; Serum; Shapes; Signal Transduction; Structure of germinal center of lymph node; Supplementation; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Vaccine Design; Work; commensal microbes; gut microbiome; improved; insight; member; microbial; microbiome; mucosal site; novel; pathogen; response; tool; vaccine development

Project Summary Plasma cells are essential to the body’s humoral immune response due to their ability to secrete antibodies that are crucial for providing immunity against systemic and mucosal pathogens. Specifically, IgA- secreting plasma cells at mucosal sites provide a critical supply of antibody for barrier functions. Recent work from our group identified that a Proteobacteria-rich microbiome induced a protective commensal-specific systemic IgA response in a sepsis model. The mechanisms that dictate the dissemination of IgA plasma cells to systemic tissues are relatively unknown and there is a need to understand how they are regulated. We found that systemic IgA induction is reliant on germinal centers. Interestingly, increased microbiome complexity induced an interferon gamma (IFN-γ) and T-bet gene expression profile in Peyer’s patch IgA+ germinal center B cells. Moreover, germinal center CD4+ T cells have an IFN-γ signature that is microbiome-dependent and localized to the Peyer’s patches. Interestingly, T-bet expression in B cells is dependent on IFN-γ signaling. Deletion of B cell-intrinsic T-bet in mice resulted in a lower frequency of bone marrow IgA+ plasma cells, demonstrating a link between systemic IgA and T-bet. Herein, our data suggests that IFN-γ signaling could be a key factor in systemic IgA induction. The central hypothesis of this proposal is that Peyer’s patch germinal center dependent IFN-γ signaling is required to drive systemic IgA. The goal of this study is to identify the role of IFN-γ in shaping B cell intrinsic T-bet expression to regulate systemic IgA responses. I will first address the hypothesis that IFN-γ signaling is necessary and sufficient to induce systemic IgA. Moreover, I will determine if B cell intrinsic T-bet expression during the germinal center reaction is responsible for the induction of systemic IgA. Ultimately, this proposal will provide a mechanism by which T-bet is inducing systemic IgA. Further, this work offers valuable insight into targeted approaches in regulating mucosal and systemic plasma responses and will improve vaccine design and development.

项目摘要 血浆细胞对于人体的体液免疫响应至关重要，因为它们的秘密能力 抗体对于提供抗系统性和粘膜病原体的免疫力至关重要。具体而言，Iga- 粘膜部位的分泌浆细胞为屏障功能提供了关键的抗体供应。最近的工作 从我们的小组中确定，富含蛋白质的微生物组诱导了受保护的共生特异性 败血症模型中的全身IgA响应。决定IgA浆细胞传播的机制 全身组织相对未知，需要了解它们的调节方式。我们发现 该系统的IgA诱导依赖于生发中心。有趣的是，微生物组的复杂性增加 在Peyer的斑块IgA+生发中心诱导了干扰素γ（IFN-γ）和T-Bet基因表达谱 B细胞。此外，生发中心CD4+ T细胞具有微生物组依赖性和 位于佩耶的补丁中。有趣的是，B细胞中的T-bet表达取决于IFN-γ信号传导。 小鼠中B细胞中的T-bet缺失导致骨髓IgA+浆细胞的频率较低， 展示系统性IGA和T-BET之间的联系。在此，我们的数据表明IFN-γ信号可能是 全身IGA诱导的关键因素。该提议的中心假设是佩耶的斑块生发中心 驱动全身IgA需要依赖性IFN-γ信号传导。这项研究的目的是确定IFN-γ的作用 在塑造B细胞固有的T-bet表达以调节全身IgA响应时。我将首先解决该假设 IFN-γ信号传导是必要的，足以诱导全身IgA。此外，我将确定B细胞是否固有 生发中心反应期间的T-bet表达负责全身IgA的诱导。最终， 该提案将提供一种诱导全身IgA的机制。此外，这项工作提供了价值 深入了解针对性方法调节粘膜和系统性血浆反应的方法，并将改善疫苗 设计与开发。