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.

项目概要 浆细胞对于人体的体液免疫反应至关重要，因为它们能够分泌 对于提供针对全身和粘膜病原体的免疫力至关重要的抗体，特别是 IgA-。 粘膜部位分泌的浆细胞为屏障功能提供了关键的抗体供应。 我们小组发现富含变形菌的微生物组诱导了保护性共生特异性 脓毒症模型中的全身 IgA 反应决定 IgA 浆细胞向体内传播的机制。 我们发现，全身组织相对未知，有必要了解它们是如何调节的。 全身 IgA 诱导依赖于生发中心。 在派尔氏斑 IgA+ 生发中心诱导干扰素 γ (IFN-γ) 和 T-bet 基因表达谱 此外，生发中心 CD4+ T 细胞具有微生物组依赖性的 IFN-γ 特征。 提示，B 细胞中的 T-bet 表达依赖于 IFN-γ 信号传导。 小鼠体内 B 细胞固有 T-bet 的缺失导致骨髓 IgA+ 浆细胞的频率降低， 证明系统性 IgA 和 T-bet 之间的联系，我们的数据表明 IFN-γ 信号传导可能是一种机制。 该提议的核心假设是派尔氏斑生发中心。 驱动全身 IgA 需要依赖 IFN-γ 信号传导。本研究的目的是确定 IFN-γ 的作用。 在塑造 B 细胞内在 T-bet 表达以调节全身 IgA 反应方面，我将首先提出这一假设。 IFN-γ 信号传导对于诱导全身性 IgA 是必要且充分的。此外，我将确定 B 细胞是否内在。 生发中心反应期间的 T-bet 表达最终负责诱导全身 IgA。 该提案将提供一种 T-bet 诱导系统性 IgA 的机制。此外，这项工作还提供了有价值的信息。 深入了解调节粘膜和全身血浆反应的靶向方法，并将改进疫苗 设计和开发。