Defining the role of T-bet in systemic IgA

项目摘要 浆细胞对人体的体液免疫反应是必不可少的，因为它们能够分泌 对提供对系统和粘膜病原体的免疫力至关重要的抗体。具体地说，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。近期工作 来自我们小组的研究人员发现，富含变形杆菌的微生物群诱导了保护性的共生特异性 脓毒症模型中的全身性IgA反应。决定免疫球蛋白A浆细胞传播到 系统性组织相对不为人所知，需要了解它们是如何被调控的。我们发现 全身性免疫球蛋白A的诱导依赖于生发中心。有趣的是，增加了微生物组的复杂性 诱导派耶氏斑块γ+生发中心干扰素-γ和T-bet基因表达谱 B细胞。此外，生发中心的CD4+T细胞有一种干扰素-γ信号，这种信号依赖于微生物组和 本地化到佩尔区。有趣的是，T-bet在B细胞中的表达依赖于干扰素-γ信号。 小鼠体内B细胞固有T-bet的缺失导致骨髓中IgA+浆细胞的频率降低， 证明了系统性免疫球蛋白A和T-BET之间的联系。在这里，我们的数据表明干扰素-γ信号可能是一种 全身免疫球蛋白A诱导的关键因素。这一提议的中心假设是Peyer的斑块生发中心 依赖的干扰素-γ信号需要驱动全身性免疫球蛋白A。本研究的目的是确定干扰素-γ的作用。 在塑造B细胞固有的T-bet表达以调节系统的IgA反应方面。我将首先提出这个假说 干扰素-γ信号是诱导全身性IgA的必要条件和充分条件。此外，我将确定B细胞是否为固有的 T-bet在生发中心反应中的表达是诱导系统性IgA的原因。最终， 这项提议将提供一种机制，通过T-bet诱导系统性IgA。此外，这项工作提供了有价值的 洞察调控黏膜和全身血浆反应的靶向方法，并将改进疫苗 设计和开发。

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.