title: Integrin-Alpha IIb Identifies Murine Lymph Node Lymphatic Endothelial Cells Responsive to RANKL.
abstract: Microenvironment and activation signals likely imprint heterogeneity in the lymphatic endothelial cell (LEC) population. Particularly LECs of secondary lymphoid organs are exposed to different cell types and immune stimuli. However, our understanding of the nature of LEC activation signals and their cell source within the secondary lymphoid organ in the steady state remains incomplete. Here we show that integrin alpha 2b (ITGA2b), known to be carried by platelets, megakaryocytes and hematopoietic progenitors, is expressed by a lymph node subset of LECs, residing in medullary, cortical and subcapsular sinuses. In the subcapsular sinus, the floor but not the ceiling layer expresses the integrin, being excluded from ACKR4+ LECs but overlapping with MAdCAM-1 expression. ITGA2b expression increases in response to immunization, raising the possibility that heterogeneous ITGA2b levels reflect variation in exposure to activation signals. We show that alterations of the level of receptor activator of NF-κB ligand (RANKL), by overexpression, neutralization or deletion from stromal marginal reticular cells, affected the proportion of ITGA2b+ LECs. Lymph node LECs but not peripheral LECs express RANK. In addition, we found that lymphotoxin-β receptor signaling likewise regulated the proportion of ITGA2b+ LECs. These findings demonstrate that stromal reticular cells activate LECs via RANKL and support the action of hematopoietic cell-derived lymphotoxin.
authors.affiliation: CNRS UPR 3572, University of Strasbourg, Laboratory of Immunopathology and Therapeutic Chemistry/ MEDALIS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Cordeiro
authors.affiliation: CNRS UPR 3572, University of Strasbourg, Laboratory of Immunopathology and Therapeutic Chemistry/ MEDALIS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.|Prestwick Chemical, Blvd Gonthier d'Andernach, Parc d'innovation, 67400, Illkirch, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Chypre
authors.affiliation: INSERM, UMR_S949, Etablissement Français du Sang-Alsace, Faculté de Médecine, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouard
authors.affiliation: CNRS UPR 3572, University of Strasbourg, Laboratory of Immunopathology and Therapeutic Chemistry/ MEDALIS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Rauber
authors.affiliation: CNRS UPR 3572, University of Strasbourg, Laboratory of Immunopathology and Therapeutic Chemistry/ MEDALIS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
authors.forename: Farouk
authors.initials: F
authors.lastname: Alloush
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Romera-Hernandez
authors.affiliation: BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bénézech
authors.affiliation: Center for Immunology and Infection, Department of Biology, University of York, York, United Kingdom.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: INSERM, UMR_S949, Etablissement Français du Sang-Alsace, Faculté de Médecine, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Eckly
authors.affiliation: Center for Immunology and Infection, Department of Biology, University of York, York, United Kingdom.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Coles
authors.affiliation: Center for Immunology and Infection, Department of Biology, University of York, York, United Kingdom.
authors.forename: Antal
authors.initials: A
authors.lastname: Rot
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: INSERM, UMR_S949, Etablissement Français du Sang-Alsace, Faculté de Médecine, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Léon
authors.affiliation: Institute of Immunobiology, Kantonspital St. Gallen, 9007, St. Gallen, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
authors.affiliation: INSERM, UMR_S949, Etablissement Français du Sang-Alsace, Faculté de Médecine, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Lanza
authors.affiliation: CNRS UPR 3572, University of Strasbourg, Laboratory of Immunopathology and Therapeutic Chemistry/ MEDALIS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mueller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D005353:Fibronectins / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology; D053308:Lymphotoxin-beta / Q000276:immunology; D008810:Mice, Inbred C57BL; D040201:Platelet Membrane Glycoprotein IIb / Q000276:immunology*; D053245:RANK Ligand / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D005353:Fibronectins; D053308:Lymphotoxin-beta; D040201:Platelet Membrane Glycoprotein IIb; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse