Orchestrating intestinal immunity through microbiota-CX3CR1+ cell interactions

项目摘要 微生物区系提供了许多支持免疫系统发育和功能的关键信号。 宿主和微生物群之间的相互作用允许适当地诱导针对病原体的免疫反应。 这些相互作用对于限制针对微生物区系的炎性免疫反应也是必要的，如果 如果不加以控制，将导致包括炎症性肠病在内的炎症状况。许多肠道细胞 包括免疫细胞和肠道上皮在内的各种类型都能识别微生物区系并对其做出反应。目前还不清楚 这些信号是如何整合在一起以支持动态平衡的。在人类和疾病的动物模型中， 微生物区系的组成变化，也被称为生物失调，与增加对 炎症性疾病。了解个体微生物在群落中的作用将允许 在炎症性疾病的情况下，开发新的机制方法来恢复体内平衡。我们 确定了一种粘膜相关的大肠杆菌亚群，可诱导肠道巨噬细胞产生IL-1b。这 激活对肠道屏障的先天保护，但也推动促炎T细胞对这些反应 大肠埃希菌。这些大肠杆菌的特定特征以及它们如何与宿主免疫系统相互作用可能 驱动着这些反应。在拟议工作的目标1中，我们将使用体外和体内模型来确定 这些大肠杆菌激活了IL-1b的产生。在目标2中，我们将定义T细胞反应的调节和结果 对这些大肠埃希菌。总之，这些研究将确定肠道微生物和 免疫系统是对抗微生物区系的促炎反应的基础。理解这些信号 将使我们能够确定调节这些途径的机制，并减少不必要的肠道 发炎。

Project Summary The microbiota provides many key signals that support development and functioning of the immune system. Interactions between host and microbiota allows for proper induction of immune responses against pathogens. These interactions are also necessary to limit inflammatory immune responses against the microbiota which, if left unchecked, will result in inflammatory conditions including inflammatory bowel disease. Many intestinal cell types including immune cells and the intestinal epithelium recognize and respond to the microbiota. It is unclear how such signals are integrated to support homeostasis. In humans as well as in animal models of disease, compositional changes in the microbiota, also known as dysbiosis, correlate with increased susceptibility to inflammatory disease. Understanding the role of individual microbes within the community would allow for the development of novel mechanistic approaches to restore homeostasis in the case of inflammatory disease. We identified a subset of mucosa associated E. coli that induce intestinal macrophage production of IL-1b. This activates innate protection of the intestinal barrier but also drives proinflammatory T cell responses against these E. coli. Specific characteristics of these E. coli as well as how they interact with the host immune system likely drives these responses. In Aim 1 of the proposed work, we will use in vitro and in vivo models to determine how these E. coli activate IL-1b production. In Aim 2 we will define the regulation and consequence of T cell responses against these E. coli. Together, these studies will identify molecular crosstalk between intestinal microbes and immune system that underlie pro-inflammatory responses against the microbiota. Understanding these signals will allow us to identify mechanisms for regulating these pathways and reducing unnecessary intestinal inflammation.