Regulation of monocyte trafficking into lymph nodes during inflammation

项目摘要/摘要 先天免疫系统的细胞在产生获得性免疫中起着不可或缺的作用。多数 值得注意的是，传统的树突状细胞在淋巴中T细胞的激活和分化中发挥着公认的作用。 炎症过程中的结节。除了树突状细胞外，其他类型的天然细胞也起到了作用。有特殊兴趣的人 是单核细胞，这是一个高度流动的细胞群体，能够获得不同的功能和命运 根据他们被招募到的组织和所遇到的炎症类型进行调整。我们最近的研究(目前 显示在接种疫苗或病毒感染期间，单核细胞迅速渗入引流淋巴结 在大量的情况下，它们在功能上与树突状细胞合作，以驱动完整的效应性T细胞 差异化。因此，在接种疫苗和感染的环境中，招募的单核细胞在塑造中发挥着深远的作用。 T细胞免疫。然而，调节单核细胞渗入淋巴结的具体机制仍然存在。 不清楚。在最近的实验中，我们发现单核细胞主要通过局部运输进入淋巴结。 血管。这些血管厚厚地排列着树突状细胞，这似乎是 单核细胞募集。炎症还会导致成分和分子图谱的显著变化 这些血管相关的树突状细胞，包括表达特定的趋化因子和黏附分子。 总而言之，这些数据导致了这一提议的中心假设，即一个专门的树突状细胞亚群 炎症时优先定位于血管附近，调节单核细胞向淋巴的运输 促进节点免疫应答的产生。 目前的提议将利用尖端成像技术、基因表达研究和功能 树突状细胞调控单核细胞的细胞和分子机制研究 在炎症期间进入淋巴结内。在特定的目标1中，我们将研究细胞和分子 稳态和炎症状态下血管相关树突状细胞的分布，并确定哪些亚群 监管单核细胞交易。在具体目标2中，我们将研究这些基因所利用的分子机制 血管相关树突状细胞促进单核细胞进入。鉴于单核细胞是一种高度可塑性的 可动员的细胞群体，能够在疫苗接种、感染、疾病和学习中发挥不同的作用 如何监管单核细胞贩运将导致疫苗和疗法设计的创新战略。

Project Summary/Abstract Cells of the innate immune system play an integral role in the generation of adaptive immunity. Most notably, conventional dendritic cells play well-established roles in T cell activation and differentiation within lymph nodes during inflammation. In addition to dendritic cells, other innate cell types also contribute. Of specific interest are monocytes, which are a highly mobile population of cells, capable of acquiring distinct functions and fates tuned to the tissue they are recruited to and the type of inflammation encountered. Our recent studies (currently in revision) reveal that during vaccination or viral infection, monocytes rapidly infiltrate the draining lymph nodes in large numbers, where they functionally cooperate with the dendritic cells to drive full effector T cell differentiation. Thus, in settings of vaccination and infection, recruited monocytes play a profound role in shaping T cell immunity. However, the specific mechanisms that regulate monocyte infiltration of the lymph nodes remain unclear. In recent experiments we have found that monocytes primarily traffic into the lymph nodes via local blood vessels. These blood vessels are heavily lined with dendritic cells, which appear to be necessary for monocyte recruitment. Inflammation also induces marked changes in both the composition and molecular profile of these vessel-associated dendritic cells, including expression of specific chemokines and adhesion molecules. Together, these data lead to the central hypothesis of this proposal, that a specialized dendritic cell subset preferentially localizes near blood vessels during inflammation and regulates monocyte trafficking into lymph nodes to promote the generation of immune responses. The current proposal will utilize cutting-edge imaging techniques, gene expression studies, and functional assays to understand the cellular and molecular mechanisms by which dendritic cells regulate monocyte trafficking into lymph nodes during inflammation. In Specific Aim 1, we will examine the cellular and molecular profile of vasculature-associated dendritic cells during steady state and inflammation, and identify which subset regulates monocyte trafficking. In Specific Aim 2, we will investigate the molecular mechanisms utilized by these vessel-associated dendritic cells to promote monocyte entry. Given that monocytes are a highly plastic and mobilizable population of cells, capable of playing diverse roles in vaccination, infection, and disease, learning how to regulate monocyte trafficking will lead to innovative strategies for the design of vaccines and therapeutics.