CD11c Dendritic Cells Regulate the Re-establishment of Vascular Quiescence and Stabilization after Immune Stimulation of Lymph Nodes

Lymph node expansion during immune responses is accompanied by rapid vascular expansion. The re-establishment of quiescence and stabilization of the newly expanded vasculature and the regulatory mechanisms involved have not been well studied. We show that although initiation of vascular expansion in immune-stimulated nodes is associated with upregulated endothelial cell proliferation , increased high endothelial venule trafficking efficiency and VCAM-1 expression, and disrupted perivascular fibroblastic reticular cell organization, the re-establishment of vascular quiescence and stabilization postexpansion is characterized by reversal of these phenomena. Although CD11c med cells are associated with the initiation of vascular expansion, CD11c hi MHC class II (MHC II) med dendritic cells (DCs) accumulate later, and their short-term depletion in mice abrogates the re-establishment of vascular quiescence and stabilization. CD11c hi MHC II med cells promote endothelial cell quiescence in vitro and, in vivo, mediate quiescence at least in part by mediating reduced lymph node vascular endothelial growth factor. Disrupted vascular quiescence and stabilization in expanded nodes is associated with attenuated T cell-dependent B cell responses. These results describe a novel mechanism whereby CD11c hi MHC II med DCs regulate the re-establishment of vascular quiescence and stabilization after lymph node vascular expansion and suggest that these DCs function in part to orchestrate the microenvironmental alterations required for successful immunity. L ymph node blood vessels are the portals of entry for circulating immune cells and play critical roles in the orchestration and regulation of immune responses. Specialized postcapillary venules with cuboidal endothelial cell morphology are termed high endothelial venules (HEVs) and mediate the constitutive trafficking of cells from the blood by displaying adhesion molecules and chemokines that allow for the rolling, adhesion, and transmigration of cells across the endothe-lium (1). During immune responses, lymph node blood vessels demonstrate functional plasticity, with transient increases in HEV trafficking capabilities and endothelial cell proliferation along with vascular expansion. These vascular changes likely serve at least in part to increase delivery of Ag-specific and other cells to optimize the developing immune response (2–7). During angio-genesis, vascular expansion is followed by vascular maturation, whereupon the newly expanded vasculature is stabilized and en-dothelial cell activity is downregulated (8–10). Studies have begun to delineate the events and regulation of early vascular activation and expansion after immune stimulation (2, 4–6, 11), but the re-establishment of vascular quiescence and stabilization post-expansion has not been well studied. Vascular expansion occurs within a few days after lymph node stimulation. …