title: Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality.
abstract: Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8+ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Novkovic
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Onder
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Jovana
authors.initials: J
authors.lastname: Cupovic
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Bomze
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Viviana
authors.initials: V
authors.lastname: Cremasco
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Elke
authors.initials: E
authors.lastname: Scandella
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.affiliation: Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Gennady
authors.identifier: 0000-0002-5049-0656
authors.initials: G
authors.lastname: Bocharov
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, California, United States of America.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054415:Chemokine CCL19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018448:Models, Immunological; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D054415:Chemokine CCL19; D016693:Receptors, Antigen, T-Cell, alpha-beta