Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

• Published in: Immunity (Cambridge, Mass.) Mass.), 2012-08, Vol.37 (2), p.276-289
• Main Authors: Acton, Sophie E., Astarita, Jillian L., Malhotra, Deepali, Lukacs-Kornek, Veronika, Franz, Bettina, Hess, Paul R., Jakus, Zoltan, Kuligowski, Michael, Fletcher, Anne L., Elpek, Kutlu G., Bellemare-Pelletier, Angelique, Sceats, Lindsay, Reynoso, Erika D., Gonzalez, Santiago F., Graham, Daniel B., Chang, Jonathan, Peters, Anneli, Woodruff, Matthew, Kim, Young-A., Swat, Wojciech, Morita, Takashi, Kuchroo, Vijay, Carroll, Michael C., Kahn, Mark L., Wucherpfennig, Kai W., Turley, Shannon J.
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Adaptive Immunity - physiology; Animals; Antigen-Presenting Cells - metabolism; Blood platelets; Blood Platelets - metabolism; Cell activation; Cell migration; Cell Movement - physiology; Cell spreading; Cells, Cultured; Chemokines; Cytoskeleton; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Development; Embryo, Mammalian; Endothelial Cells - metabolism; Endothelium, Lymphatic - cytology; Endothelium, Lymphatic - metabolism; Female; Flow Cytometry; Glycoproteins; Green Fluorescent Proteins - metabolism; Humans; Lectins; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lectins, C-Type - metabolism; Lymph nodes; Lymph Nodes - cytology; Lymph Nodes - metabolism; Lymphocytes T; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy; Microscopy, Confocal; Migration; Motility; Myosin; Myosin Light Chains - metabolism; Phosphorylation; Platelet Activation; Platelets; Pregnancy; Proto-Oncogene Proteins c-vav - metabolism; rac1 GTP-Binding Protein - metabolism; Rac1 protein; rhoA GTP-Binding Protein - metabolism; RhoA protein; scaffolds; Scholarships & fellowships; Signal Transduction - physiology; Skin - cytology; Skin - metabolism; Statistical analysis; Tissue Culture Techniques
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2012.05.022

To 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. ► The CLEC-2-PDPN interaction promotes DC migration to LNs ► CLEC-2 activation induces actin-rich protrusions and motility in DCs ► CLEC-2 activation reduces actomyosin contraction and promotes actin polymerization