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.
During vaccination and viral infection, monocytes that infiltrate the draining lymph nodes play an integral role in the generation of adaptive immunity, but the specific mechanisms of how they traffic to the lymph nodes is unclear. Our preliminary studies suggest that this process is regulated by dendritic cells that line the local blood vessels within lymph nodes during inflammation. Using cutting-edge imaging, gene expression analysis, and functional studies, we will investigate the spatiotemporal dynamics of monocyte trafficking into inflamed lymph nodes and define the mechanisms of this novel function of dendritic cells in facilitating this process, thus providing critical information for the design of vaccines and therapeutics
