Regulation of monocyte trafficking into lymph nodes during inflammation

项目总结/摘要 先天免疫系统的细胞在适应性免疫的产生中起着不可或缺的作用。最 值得注意的是，传统的树突状细胞在淋巴内的T细胞活化和分化中发挥着公认的作用， 炎症期间的结节。除了树突状细胞，其他先天细胞类型也有贡献。具体关注的 是单核细胞，其是高度移动的细胞群体，能够获得不同的功能和命运 根据他们被招募的组织和遇到的炎症类型进行调整。我们最近的研究（目前 在修订中）揭示了在接种疫苗或病毒感染期间，单核细胞迅速浸润引流淋巴结 在大量的情况下，它们在功能上与树突状细胞合作， 分化因此，在疫苗接种和感染的情况下，募集的单核细胞在塑造免疫缺陷方面发挥着重要作用。 T细胞免疫然而，调节淋巴结单核细胞浸润的特定机制仍然存在 不清楚在最近的实验中，我们发现单核细胞主要通过局部的淋巴结转运进入淋巴结。 血管这些血管里布满了树突状细胞，这似乎是必要的， 单核细胞募集炎症也会引起组成和分子特征的显著变化 这些血管相关的树突状细胞，包括表达特定的趋化因子和粘附分子。 总之，这些数据导致了这一提议的中心假设，即一个专门的树突细胞亚群 在炎症期间优先定位于血管附近，并调节单核细胞向淋巴中的运输 节点，以促进免疫反应的产生。 目前的建议将利用尖端的成像技术，基因表达研究，和功能 了解树突状细胞调节单核细胞的细胞和分子机制的试验 在炎症期间进入淋巴结。在具体目标1中，我们将检查细胞和分子 稳态和炎症期间血管相关树突状细胞的特征，并确定哪个亚群 调节单核细胞运输。在具体目标2中，我们将研究这些分子所利用的分子机制。 血管相关树突状细胞，以促进单核细胞进入。考虑到单核细胞是一种高度可塑性的细胞， 可动员的细胞群，能够在疫苗接种、感染和疾病中发挥多种作用， 如何调节单核细胞的运输将导致设计疫苗和治疗方法的创新策略。

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.