Lymphoid Tissue Vascular-Stromal Regulation and Function
Secondary lymphoid tissues such as lymph nodes are the sites of primary immune responses. These lymphoid tissues grow rapidly and robustly during an immune response, and this growth is accompanied by growth of the blood vessels. Although work in recent years has delineated the regulation of vascular growth in a number of systems, the regulation of lymphoid tissue vessel growth is not well understood. However, because blood vessels of the lymphoid tissues are critical for the delivery of oxygen, micronutrients, and cells, manipulating the growth of blood vessels may be a means to manipulate immune function.
We have identified a role for dendritic or other CD11c+ cells and for fibroblastic reticular cells in regulating lymph node vascular growth. In lymph nodes, blood vessels are suspended in a reticular network composed of collagen-rich fibrils that are ensheathed by fibroblastic reticular cells. We have shown that fibroblastic reticular cells are the main VEGF mRNA-expressing cell type within lymph nodes. Dendritic cells are directly attached to the reticular network and are enriched in vessel-rich areas. Our model is currently that dendritic cells that are activated by the immune stimulus induce fibroblastic reticular cells to upregulate VEGF, which leads to endothelial cell proliferation. Dendritic cells are best known for their function in presenting antigen to T cells; we propose that also play a role in preparing the lymph node vascular-stromal microenvironment for the ensuing immune response.
After vascular expansion, there is a stage of vascular quiescence and stabilization whereby proliferation of the newly expanded vasculature is downregulated and the vessels are made less leaky. We have identified a role for a distinct subset of late-accumulating dendritic cells in regulating vascular quiescence and stabilization and are currently trying to understand how these dendritic cells work. We have also shown that disruption of vascular quiescence and stabilization is associated with disrupted B cell responses. Abnormal B cell responses in autoimmune diseases such as lupus lead to the generation of pathogenic autoantibodies which cause inflammation in skin, kidney and other internal organs. We are testing the possibility that disruption of vascular quiescence and stabilization could be a novel means by which to control pathogenic autoantibody generation.