In vivo functions of distinct CD103+ intestinal dendritic cell subsets

描述（由申请人提供）：树突状细胞（DC）是特化的抗原呈递细胞（APC），对启动和调节适应性免疫反应至关重要。尽管不同的DC亚群存在于周围组织中，但它们的功能作用仍然知之甚少。在肠道中，有两个主要的APC群体可以通过CX3CR1和CD103的表面表达来定义。CX3CR1被认为是一种非迁移的巨噬细胞样群体。相比之下，CD103+ DC迁移到肠系膜淋巴结，在那里它们执行经典的DC功能。在体外，迁移的CD103+ DC可以诱导调节性T细胞，提示免疫系统可以耐受正常肠道内容物的机制。最近人们认识到，CD103+ DC群体实际上包含两个不同的亚群，以CD11b的表达来区分。我们已经产生了选择性切除CD103+CD11b+亚群的小鼠，并将它们与先前描述的缺乏CD103+CD11b- DC的小鼠杂交。通过比较缺乏一种或两种DC的小鼠，本研究旨在确定每个亚群在体内的精确功能作用。我们的中心假设是，这两个CD103+群体对于耐受性的发展是相互冗余的。然而，在感染的情况下，我们假设CD11b+ DC是先天粘膜防御和Th17反应发展所必需的，而CD11b- DC介导Th1免疫。因此，这项研究对我们理解肠道免疫稳态和对肠道病原体的免疫反应具有重要意义。

DESCRIPTION (provided by applicant): Dendritic cells (DC) are specialized antigen presenting cells (APC) that are critical for initiating and regulating adaptive immune responses. Although distinct DC subsets are present throughout peripheral tissues, their functional roles remain poorly understood. In the intestine there are two major APC populations that can be defined by the surface expression of CX3CR1 and CD103. CX3CR1 are thought to be a non-migratory macrophage-like population. In contrast, CD103+ DC migrate to mesenteric lymph nodes, where they carry out classical DC functions. In vitro, migrated CD103+ DC can induce regulatory T cells, suggesting a mechanism whereby the immune system can become tolerant to normal intestinal contents. It has recently been appreciated that the CD103+ DC population actually contains two distinct subsets distinguished by CD11b expression. We have generated mice with a selective ablation of the CD103+CD11b+ subset and have bred them with previously described mice that lack CD103+CD11b- DC. By comparing mice lacking one or both DC, this proposal seeks to determine the precise functional role of each subset in vivo. Our central hypothesis is that these two CD103+ populations are mutually redundant for the development of tolerance. However, in the setting of infection, we hypothesize that CD11b+ DC are required for innate mucosal defense and the development of Th17 responses, while CD11b- DC mediate Th1 immunity. This study thus has important implications for our understanding of intestinal immune homeostasis and immune responses to gut pathogens. PUBLIC HEALTH RELEVANCE: Project Narrative Tissue resident dendritic cells control the balance of immune tolerance versus inflammation. This study will uncover the ability of unique intestinal dendritic cell populations to generate appropriate immune responses in both the steady state and disease.