title: Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2.
abstract: 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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Acton
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Astarita
authors.forename: Deepali
authors.initials: D
authors.lastname: Malhotra
authors.forename: Veronika
authors.initials: V
authors.lastname: Lukacs-Kornek
authors.forename: Bettina
authors.initials: B
authors.lastname: Franz
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hess
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Jakus
authors.forename: Michael
authors.initials: M
authors.lastname: Kuligowski
authors.forename: Anne L
authors.initials: AL
authors.lastname: Fletcher
authors.forename: Kutlu G
authors.initials: KG
authors.lastname: Elpek
authors.forename: Angelique
authors.initials: A
authors.lastname: Bellemare-Pelletier
authors.forename: Lindsay
authors.initials: L
authors.lastname: Sceats
authors.forename: Erika D
authors.initials: ED
authors.lastname: Reynoso
authors.forename: Santiago F
authors.initials: SF
authors.lastname: Gonzalez
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Anneli
authors.initials: A
authors.lastname: Peters
authors.forename: Matthew
authors.initials: M
authors.lastname: Woodruff
authors.forename: Young-A
authors.initials: YA
authors.lastname: Kim
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Vijay
authors.initials: V
authors.lastname: Kuchroo
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
mesh_terms: D000199:Actins / Q000378:metabolism; D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018994:Myosin Light Chains / Q000378:metabolism; D015539:Platelet Activation; D011247:Pregnancy; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000378:metabolism; D046509:Tissue Culture Techniques; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D000199:Actins; D049452:Green Fluorescent Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D018994:Myosin Light Chains; D051567:Proto-Oncogene Proteins c-vav; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C529518:CLEC-2 protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin