Abstract
SummaryTo initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Highlights
Cell motility is crucial for trafficking of leukocytes between tissues and for their interaction with one another and their microenvironment
Previous studies have shown that dendritic cells (DCs) make contact with lymphatic endothelial cells (LECs) upon emigrating from peripheral tissues (Baluk et al, 2007; Stoitzner et al, 2002); it has not been previously demonstrated whether DCs make direct contact with LECs or fibroblastic reticular cells (FRCs) in vivo
LECs and FRCs, which line the structures that DCs utilize during migration to the T cell zone of the lymph nodes (LNs), express PDPN at their surfaces (Farr et al, 1992)
Summary
Cell motility is crucial for trafficking of leukocytes between tissues and for their interaction with one another and their microenvironment. The only wellestablished directional cues guiding tissue-derived DCs to the LN paracortex are the chemokines CCL19 and CCL21 (Forster et al, 1999; Schumann et al, 2010), two CCR7 ligands expressed by lymphatic endothelial cells (LECs) and FRCs (Link et al, 2007). How these chemokines act as functional gradients across such vast distances has not been adequately explained, which raises the question of whether additional hitherto-undiscovered migration mechanisms may be involved. The specific molecules that support amoeboid movement and initiate cytoskeletal rearrangements to cause spreading and translocation of DCs along stromal scaffolds remain elusive
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