title: Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses.
abstract: Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell-cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2-driven differentiation of marginal zone B cells and of Esam(+) dendritic cells. Moreover, conditional inactivation of DL4 in lymph node fibroblasts resulted in impaired follicular helper T cell differentiation and, consequently, in reduced numbers of germinal center B cells and absence of high-affinity antibodies. Our data demonstrate previously unknown roles for DL ligand-expressing fibroblasts in SLO niches as drivers of multiple Notch-mediated immune differentiation processes.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research, 1015 Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fasnacht
authors.affiliation: Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Hsin-Ying
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research, 1015 Lausanne, Switzerland.
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.affiliation: Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Favre
authors.affiliation: Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Floriane
authors.initials: F
authors.lastname: Auderset
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chai
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Onder
authors.affiliation: Department of Biomedicine - Haus Petersplatz, Division of Experimental Virology, University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kallert
authors.affiliation: Department of Biomedicine - Haus Petersplatz, Division of Experimental Virology, University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.affiliation: Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald
authors.affiliation: Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
authors.affiliation: Department of Biochemistry, WHO Immunology Research and Training Center, and Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland Freddy.Radtke@epfl.ch sanjiv.luther@unil.ch.
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research, 1015 Lausanne, Switzerland Freddy.Radtke@epfl.ch sanjiv.luther@unil.ch.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D060833:Cellular Microenvironment / Q000276:immunology*; D054415:Chemokine CCL19 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007109:Immunity; D016130:Immunophenotyping; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D054415:Chemokine CCL19; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; C428190:Esam protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch