Defining the role of T-bet in systemic IgA

项目摘要 浆细胞是必不可少的身体的体液免疫反应，由于他们的能力，分泌 这些抗体对于提供针对全身性和粘膜病原体的免疫至关重要。具体来说，伊加- 在粘膜部位分泌浆细胞为屏障功能提供关键的抗体供应。最近的工作 来自我们小组的研究人员发现，富含变形菌的微生物组诱导了一种保护性的细菌特异性 脓毒症模型中的全身性伊加应答。决定伊加浆细胞播散至 系统性组织相对未知，需要了解它们是如何调节的。我们发现 系统性伊加诱导依赖于生殖中心。有趣的是，微生物组复杂性的增加 在派伊尔集合淋巴结伊加+生发中心诱导干扰素γ（IFN-γ）和T-bet基因表达谱 B细胞。此外，生发中心CD 4 + T细胞具有IFN-γ特征，其是微生物组依赖性的， 局限于派尔集合淋巴结有趣的是，B细胞中的T-bet表达依赖于IFN-γ信号传导。 小鼠中B细胞固有T-bet的缺失导致骨髓伊加+浆细胞的频率降低， 证明了全身性伊加和T-bet之间的联系。在此，我们的数据表明，IFN-γ信号可能是一个重要的信号通路。 系统性伊加诱导关键因素。这个建议的中心假设是，派尔斑germination中心 需要依赖性IFN-γ信号传导来驱动系统性伊加。本研究的目的是确定IFN-γ的作用 在形成B细胞内在T-bet表达以调节系统性伊加应答中的作用。我首先要说明的是 IFN-γ信号传导是诱导全身性伊加所必需的和充分的。此外，我将确定是否B细胞内在 在生发中心反应期间的T-bet表达负责全身性伊加的诱导。最后， 该建议将提供T-bet诱导全身性伊加的机制。此外，这项工作提供了宝贵的 深入了解调节粘膜和全身血浆反应的靶向方法， 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.