Abstract
Microenvironment and activation signals likely imprint heterogeneity in the lymphatic endothelial cell (LEC) population. Particularly LECs of secondary lymphoid organs are exposed to different cell types and immune stimuli. However, our understanding of the nature of LEC activation signals and their cell source within the secondary lymphoid organ in the steady state remains incomplete. Here we show that integrin alpha 2b (ITGA2b), known to be carried by platelets, megakaryocytes and hematopoietic progenitors, is expressed by a lymph node subset of LECs, residing in medullary, cortical and subcapsular sinuses. In the subcapsular sinus, the floor but not the ceiling layer expresses the integrin, being excluded from ACKR4+ LECs but overlapping with MAdCAM-1 expression. ITGA2b expression increases in response to immunization, raising the possibility that heterogeneous ITGA2b levels reflect variation in exposure to activation signals. We show that alterations of the level of receptor activator of NF-κB ligand (RANKL), by overexpression, neutralization or deletion from stromal marginal reticular cells, affected the proportion of ITGA2b+ LECs. Lymph node LECs but not peripheral LECs express RANK. In addition, we found that lymphotoxin-β receptor signaling likewise regulated the proportion of ITGA2b+ LECs. These findings demonstrate that stromal reticular cells activate LECs via RANKL and support the action of hematopoietic cell-derived lymphotoxin.
Highlights
Molecules, cells and pathogens carried by the lymph flow are filtered by lymph nodes (LNs)
We tested whether the integrin could be detected on FACS-sorted lymphatic endothelial cell (LEC) grown in culture
Labelled LECs but not the other stromal subsets (Fig 1F). These finding demonstrated that LN LECs, but not other stromal cells, express the integrin alpha 2b (ITGA2b) integrin
Summary
Cells and pathogens carried by the lymph flow are filtered by lymph nodes (LNs). In these specialized organs, resident immune cells recognize, eliminate and mount an immune response against pathogens. The LECs provide an important structural and functional support to this process by mediating lymph drainage, organizing cellular compartments, regulating the immune response and controlling lymph exit [1]. Differential expression of the chemokine ACKR4 ( called CCRL1) has recently highlighted structural and functional specialization of these layers [2]. LECs form the cortical and medullary sinuses that allow distribution of cells and large molecules within different LN compartments and exit into the efferent lymph [3]. Platelet adhesion to lymphatic endothelium mediates blood and lymphatic vessel separation during embryonic development [4]
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