title: Dendritic cells control fibroblastic reticular network tension and lymph node expansion.
abstract: After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellularity, leading to organ expansion. Here we report that the physical elasticity of lymph nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes also initiate remodelling of lymph nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph node expansion--driven by lymphocyte influx and proliferation--that is the critical hallmark of adaptive immunity.
authors.affiliation: 1] Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Acton
authors.affiliation: 1] Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Farrugia
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Astarita
authors.affiliation: Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Mourão-Sá
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jenkins
authors.affiliation: Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Hooper
authors.affiliation: Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Janneke
authors.initials: J
authors.lastname: van Blijswijk
authors.affiliation: Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Rogers
authors.affiliation: Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Snelgrove
authors.affiliation: Transgenics Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Rosewell
authors.affiliation: 1] Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal [2] Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Moita
authors.affiliation: Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.affiliation: Department of Cancer Immunology, Genentech, One DNA Way, South San Francisco, California 94080, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Caetano
authors.initials: C
authors.lastname: Reis e Sousa
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D007249:Inflammation / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D017154:Stromal Cells / Q000166:cytology* / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein; D000098853:Podoplanin
chemical_list: D000205:Actomyosin; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein; C529518:CLEC-2 protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C526380:RhoA protein, mouse; C512911:Rhoc protein, mouse