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.

项目总结