Defining host interactions with lymphoid tissue-resident commensal bacteria

总结 针对肠道细菌的免疫应答失调与发病机制有关， 多种胃肠道疾病的进展，并保持身体之间的分离， 细菌和哺乳动物免疫系统可以防止这种炎症反应。然而，最近的报告 证明选择性的肠道细菌物种可以驻留在肠道相关的内部， 健康人、非人灵长类动物和小鼠的淋巴组织。这种独特的殖民化是如何发生的， 对免疫系统的功能影响尚不清楚。在新的初步数据中，我们证明淋巴 组织驻留细菌（LRC）可以定殖小鼠树突状细胞并调节细胞因子的产生。 在无菌和驱虫处理的（ABX）小鼠中，LRC定植于膀胱相关淋巴组织，并诱导 IL-10细胞因子家族的多个成员，包括树突状细胞衍生的IL-10和第3组先天性淋巴细胞因子。 细胞（ILC 3）衍生的IL-22。值得注意的是，IL-10限制促炎性Th 17细胞应答的发展， IL-22的产生增强了稳态下的LRC定殖。此外，LRC定殖保护小鼠 以IL-10-IL-10 R依赖的方式从致死性肠损伤中恢复。总的来说，我们的数据揭示了一种新的宿主- 树突状细胞与选择性的树突状细胞相互作用， 促进对宿主和微生物都有利的组织特异性反应。 这些发现引发了一个中心假设，即LRC与哺乳动物树突状细胞的相互作用至关重要， 调节胃肠道的慢性炎症。我们将运用这些方法来定义小说 LRC和哺乳动物树突状细胞在肠道健康背景下的功能相互作用， 疾病该项目的两个具体目标将确定（i）LRC是否调节宿主一氧化氮的产生， 持续存在于DC内并影响肠损伤和炎症，以及（ii）DC调节细胞内的 铁调节肠道健康和疾病期间LRC定植和随后的细胞因子产生？ 总的来说，这些研究将系统地询问一个未被重视的 寄生细菌和哺乳动物宿主的纲。这些研究将为正在进行的努力提供信息， 针对微生物群的有效疗法，以限制慢性胃肠道疾病。

Summary Dysregulated immune responses against commensal bacteria are associated with the pathogenesis or progression of multiple gastrointestinal diseases, and maintaining physical separation between commensal bacteria and the mammalian immune system can prevent this inflammatory response. However, recent reports demonstrate that selective species of commensal bacteria can reside on the interior of intestinal-associated lymphoid tissues of healthy humans, non-human primates and mice. How this unique colonization occurs and functionally influences the immune system is unclear. In new preliminary data, we demonstrate that lymphoid tissue-resident commensal bacteria (LRC) can colonize murine dendritic cells and modulate cytokine production. In germ-free and antibiotic-treated (ABX) mice, LRCs colonize intestinal-associated lymphoid tissues and induce multiple members of the IL-10 cytokine family, including dendritic cell-derived IL-10 and group 3 innate lymphoid cell (ILC3)-derived IL-22. Notably, IL-10 limits the development of pro-inflammatory Th17 cell responses, and IL-22 production enhances LRC colonization in the steady state. Furthermore, LRC colonization protects mice from lethal intestinal damage in an IL-10-IL-10R-dependent manner. Collectively, our data reveal a novel host- commensal bacteria dialogue whereby selective subsets of commensal bacteria interact with dendritic cells to facilitate tissue-specific responses that are mutually beneficial for both the host and the microbe. These findings provoke the central hypothesis that LRC interactions with mammalian dendritic cells critically modulate chronic inflammation in the gastrointestinal tract. We will employ theses approaches to define novel functional interactions between LRCs and mammalian dendritic cells in the context of intestinal health and disease. Two specific aims of this project will determine (i) Do LRCs modulate host nitric oxide production to persist within DCs and influence intestinal damage and inflammation, and (ii) Does DC regulation of intracellular iron modulate colonization by LRCs and subsequent cytokine production during intestinal health and disease? Collectively, these studies will systematically interrogate novel functional interactions between an unappreciated class of commensal bacteria and mammalian hosts. These studies will inform ongoing efforts to develop effective therapies targeting the microbiota to limit chronic gastrointestinal diseases.