title: The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture.
abstract: In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.
authors.affiliation: 1] Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Astarita
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Cremasco
authors.affiliation: 1] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. [2] Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Jianxin
authors.identifier: 0000000230678539
authors.initials: J
authors.lastname: Fu
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. [2] Wyss Institute for Biologically Inspired Engineering at Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Max C
authors.initials: MC
authors.lastname: Darnell
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Peck
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Nieves-Bonilla
authors.affiliation: 1] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. [2] Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Song
authors.affiliation: 1] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. [2] Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: 1] Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Woodruff
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, California, USA.
authors.forename: Alvin
authors.initials: A
authors.lastname: Gogineni
authors.affiliation: Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Onder
authors.affiliation: Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, California, USA.
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. [2] Wyss Institute for Biologically Inspired Engineering at Harvard University, Cambridge, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
authors.affiliation: 1] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. [2] Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Lijun
authors.identifier: 0000000295867971
authors.initials: L
authors.lastname: Xia
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Cancer Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000276:immunology; D003094:Collagen / Q000276:immunology / Q000378:metabolism*; D003599:Cytoskeleton / Q000276:immunology / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000276:immunology / Q000648:ultrastructure; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology / Q000648:ultrastructure; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D000098853:Podoplanin
chemical_list: D000577:Amides; D003094:Collagen; D004791:Enzyme Inhibitors; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011725:Pyridines; C529518:CLEC-2 protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C108830:Y 27632