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.