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Fibroblasts of lymphoid tissues: from phenotype to function

English title Fibroblasts of lymphoid tissues: from phenotype to function
Applicant Luther Sanjiv
Number 166161
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Immunology, Immunopathology
Start/End 01.05.2016 - 31.08.2019
Approved amount 600'000.00
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Keywords (6)

T cell activation; immune regulation; lymph node; fibroblastic reticular cells; organ development; spleen

Lay Summary (German)

Lead
Die Lymphknoten und Milz sind wichtige Organe fuer die Aktivierung von T und B Lymphozyten. Ueber die letzten 20-30 Jahre haben wir grosse Fortschritte gemacht im Verständnis, wie Lymphozyten funktionieren. Noch relativ wenig erforscht sind die nicht-hematopoietischen Zellen in diesen Organen, inklusive Blut- und Lymphgefässe so wie auch die verschiedenen Fibroblasten. Dieses Projekt zielt auf eine bessere phenotypische und funktionelle Charakterisierung der Fibroblasten im Lymphknoten der Maus ab.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Fibroblasten machen ein schwammartiges 3-dimensionales Netzwerk in der T Zell Zone, wo T Lymphozyten mit den dendritischen Zellen zusammentreffen. Sie sind nicht nur fuer die Struktur und Stabilität dieser Region verantwortlich, sondern formen ein ‚Strassensystem’ und ‚Adhesionsgerüst’ fuer Lymphozyten und dendritische Zellen. Wir konnten zeigen, dass diese Fibroblasten aktiv diese Zellen anziehen und in der T Zell Zone halten können, indem sie chemotaktische Faktoren wie CCL19/21 produzieren können. Sie machen auch Faktoren, die T Lymphozyten am Leben halten (IL-7) oder sie an der zu starken Vermehrung hindern (Prostanoide, Stickstoffmonoxid). Vor kurzem wurde auch gezeigt, dass diese Fibroblasten sehr viele verschiedene lösliche Faktoren machen, welche auf Lymphozyten und dendritische Zellen wirken können.

Um diese Fibroblasten im Lymphknoten der Maus studieren zu können, haben wir etliche Methoden und Werkzeuge entwickelt und charakterisiert, inklusive Methoden zur Isolation, Faerbung, Kultivierung und Immortalisierung, so wie auch neue Mausmodelle. Die Expertise, die wir in diesem Feld aufgebaut haben, bildet die Grundlage, um die folgenden Fragestellungen anzugehen, welche sich alle um die Lymphknoten Fibroblasten der Maus drehen:

1) Wie regulieren sie die Antwort oder ‚Toleranz’ der T Lymphozyten?

2) Was passiert, wenn wir spezifisch in diesen Zellen ein Gen entfernen, was möglicherweise für ihre Entwicklung oder Funktion wichtig ist?

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Dieses Projekt befasst sich mit Grundlagenforschung in der Maus. In Zukunft planen wir, die neuen Erkenntnisse aus Mausexperimenten in menschlichen Lymphknoten zu verifizieren. Wir glauben, dass ein besseres Verständnis dieser Fibroblasten uns erlauben sollte, die Immunantwort zu verstärken so wie im Falle einer Infektion, oder sie abzuschwächen, so wie in einer Autoimmunerkrankung oder chronischen Entzündung.

Direct link to Lay Summary Last update: 19.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts
Schaeuble Karin, Cannelle Hélène, Favre Stéphanie, Huang Hsin-Ying, Oberle Susanne G., Speiser Daniel E., Zehn Dietmar, Luther Sanjiv A. (2019), Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts, in {PLOS} Biology, 17(7), 3000072-3000072.
IL-4Rα-Expressing B Cells Are Required for CXCL13 Production by Fibroblastic Reticular Cells.
LK Dubey, B Ludewig, SA Luther, NL Harris (2019), IL-4Rα-Expressing B Cells Are Required for CXCL13 Production by Fibroblastic Reticular Cells., in Cell reports, 2442.
Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.
S Nayar, J Campos, CG Smith, V Iannizzotto, DH Gardner, F Mourcin, D Roulois, J Turner, M Sylvestre, S Asam, B Glaysher, SJ Bowman, DT Fearon, F Barone (2019), Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology., in Proceedings of the National Academy of Sciences of the United States of America, 13490.
Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy.
I Siddiqui, K Schaeuble, V Chennupati, SA Fuertes Marraco, S Calderon-Copete, D Pais Ferreira, SJ Carmona, L Scarpellino, D Gfeller, S Pradervand, W Held (2019), Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy., in Immunity, 195.
Formation of the Intrathymic Dendritic Cell Pool Requires CCL21-Mediated Recruitment of CCR7+Progenitors to the Thymus
Cosway Emilie J., Ohigashi Izumi, Schauble Karin, Parnell Sonia M., Jenkinson William E., Luther Sanjiv, Takahama Yousuke, Anderson Graham (2018), Formation of the Intrathymic Dendritic Cell Pool Requires CCL21-Mediated Recruitment of CCR7+Progenitors to the Thymus, in The Journal of Immunology, 201(2), 516-523.
Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis
Huang Hsin-Ying, Rivas-Caicedo Ana, Renevey François, Cannelle Hélène, Peranzoni Elisa, Scarpellino Leonardo, Hardie Debbie L, Pommier Arnaud, Schaeuble Karin, Favre Stéphanie, Vogt Tobias K, Arenzana-Seisdedos Fernando, Schneider Pascal, Buckley Christopher D, Donnadieu Emmanuel, Luther Sanjiv A (2018), Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis, in Proceedings of the National Academy of Sciences of the United States of America, 115(29), 6826-6835.
Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.
A Wilson, H Fu, M Schiffrin, C Winkler, M Koufany, JY Jouzeau, N Bonnet, F Gilardi, F Renevey, SA Luther, D Moulin, B Desvergne (2018), Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice., in Frontiers in immunology, 2573.
Manifold Roles of CCR7 and Its Ligands in the Induction and Maintenance of Bronchus-Associated Lymphoid Tissue
Fleige Henrike, Bosnjak Berislav, Permanyer Marc, Ristenpart Jasmin, Bubke Anja, Willenzon Stefanie, Sutter Gerd, Luther Sanjiv A, Förster Reinhold (2018), Manifold Roles of CCR7 and Its Ligands in the Induction and Maintenance of Bronchus-Associated Lymphoid Tissue, in Cell reports, 23(3), 783-795.
Multiple roles of lymphatic vessels in peripheral lymph node development.
E Bovay, A Sabine, B Prat-Luri, S Kim, K Son, AH Willrodt, C Olsson, C Halin, F Kiefer, C Betsholtz, NL Jeon, SA Luther, TV Petrova (2018), Multiple roles of lymphatic vessels in peripheral lymph node development., in The Journal of experimental medicine, 2760.
Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity
Rodda Lauren B, Lu Erick, Bennett Mariko L, Sokol Caroline L, Wang Xiaoming, Luther Sanjiv A, Barres Ben A, Luster Andrew D, Ye Chun Jimmie, Cyster Jason G (2018), Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity, in Immunity, 48(5), 1014-1028.
TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection.
C Ronet, K Passelli, M Charmoy, L Scarpellino, E Myburgh, Y Hauyon La Torre, S Turco, JC Mottram, N Fasel, SA Luther, SM Beverley, P Launois, F Tacchini-Cottier (2018), TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection., in The Journal of investigative dermatology, 1318.
A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development
Boege Yannick, Malehmir Mohsen, Healy Marc E, Bettermann Kira, Lorentzen Anna, Vucur Mihael, Ahuja Akshay K, Böhm Friederike, Mertens Joachim C, Shimizu Yutaka, Frick Lukas, Remouchamps Caroline, Mutreja Karun, Kähne Thilo, Sundaravinayagam Devakumar, Wolf Monika J, Rehrauer Hubert, Koppe Christiane, Speicher Tobias, Padrissa-Altés Susagna, Maire Renaud, Schattenberg Jörn M, Jeong Ju-Seong, Liu Lei, Zwirner Stefan, Boger Regina, Hüser Norbert, Davis Roger J, Müllhaupt Beat, Moch Holger, Schulze-Bergkamen Henning, Clavien Pierre-Alain, Werner Sabine, Borsig Lubor, Luther Sanjiv A, Jost Philipp J, Weinlich Ricardo, Unger Kristian, Behrens Axel, Hillert Laura, Dillon Christopher, Di Virgilio Michela, Wallach David, Dejardin Emmanuel, Zender Lars, Naumann Michael, Walczak Henning, Green Douglas R, Lopes Massimo, Lavrik Inna, Luedde Tom, Heikenwalder Mathias, Weber Achim (2017), A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development, in Cancer cell, 32(3), 342-359.
Essential role of CCL21 in establishment of central self-tolerance in T cells
Kozai Mina, Kubo Yuki, Katakai Tomoya, Kondo Hiroyuki, Kiyonari Hiroshi, Schaeuble Karin, Luther Sanjiv A, Ishimaru Naozumi, Ohigashi Izumi, Takahama Yousuke (2017), Essential role of CCL21 in establishment of central self-tolerance in T cells, in The Journal of experimental medicine, 214(7), 1925-1935.
Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands
Chung Jooho, Ebens Christen L, Perkey Eric, Radojcic Vedran, Koch Ute, Scarpellino Leonardo, Tong Alexander, Allen Frederick, Wood Sherri, Feng Jiane, Friedman Ann, Granadier David, Tran Ivy T, Chai Qian, Onder Lucas, Yan Minhong, Reddy Pavan, Blazar Bruce R, Huang Alex Y, Brennan Todd V, Bishop D Keith, Ludewig Burkhard, Siebel Christian W, Radtke Freddy, Luther Sanjiv A, Maillard Ivan (2017), Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands, in The Journal of clinical investigation, 127(4), 1574-1588.
Interactions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis
Dubey Lalit Kumar, Karempudi Praneeth, Luther Sanjiv A, Ludewig Burkhard, Harris Nicola L (2017), Interactions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis, in Nature communications, 8(1), 367-367.
Perivascular Fibroblasts of the Developing Spleen Act as LTα1β2-Dependent Precursors of Both T and B Zone Organizer Cells
Schaeuble Karin, Britschgi Mirjam R, Scarpellino Leo, Favre Stéphanie, Xu Ying, Koroleva Ekaterina, Lissandrin Tonje K A, Link Alexander, Matloubian Mehrdad, Ware Carl F, Nedospasov Sergei A, Tumanov Alexei V, Cyster Jason G, Luther Sanjiv A (2017), Perivascular Fibroblasts of the Developing Spleen Act as LTα1β2-Dependent Precursors of Both T and B Zone Organizer Cells, in Cell reports, 21(9), 2500-2514.
Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy
Kallert Sandra M, Darbre Stephanie, Bonilla Weldy V, Kreutzfeldt Mario, Page Nicolas, Müller Philipp, Kreuzaler Matthias, Lu Min, Favre Stéphanie, Kreppel Florian, Löhning Max, Luther Sanjiv A, Zippelius Alfred, Merkler Doron, Pinschewer Daniel D (2017), Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy, in Nature communications, 8, 15327-15327.
CCL19-CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima
Roufaiel Mark, Gracey Eric, Siu Allan, Zhu Su-Ning, Lau Andrew, Ibrahim Hisham, Althagafi Marwan, Tai Kelly, Hyduk Sharon J, Cybulsky Kateryna O, Ensan Sherine, Li Angela, Besla Rickvinder, Becker Henry M, Xiao Haiyan, Luther Sanjiv A, Inman Robert D, Robbins Clinton S, Jongstra-Bilen Jenny, Cybulsky Myron I (2016), CCL19-CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima, in Nature immunology, 17(11), 1263-1272.
CD8 engineered cytotoxic T cells reprogram melanoma tumor environment
Leignadier Julie, Favre Stephanie, Luther Sanjiv A, Luescher Immanuel F (2016), CD8 engineered cytotoxic T cells reprogram melanoma tumor environment, in Oncoimmunology, 5(3), 1086861-1086861.
Lymphotoxin-Dependent B Cell-FRC Crosstalk Promotes De Novo Follicle Formation and Antibody Production following Intestinal Helminth Infection
Dubey Lalit Kumar, Lebon Luc, Mosconi Ilaria, Yang Chen-Ying, Scandella Elke, Ludewig Burkhard, Luther Sanjiv A, Harris Nicola L (2016), Lymphotoxin-Dependent B Cell-FRC Crosstalk Promotes De Novo Follicle Formation and Antibody Production following Intestinal Helminth Infection, in Cell reports, 15(7), 1527-1541.
Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells
Chennupati Vijaykumar, Koch Ute, Coutaz Manuel, Scarpellino Leonardo, Tacchini-Cottier Fabienne, Luther Sanjiv A, Radtke Freddy, Zehn Dietmar, MacDonald H Robson (2016), Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells, in Journal of immunology (Baltimore, Md. : 1950), 197(3), 771-782.
Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation
Barone Francesca, Gardner David H, Nayar Saba, Steinthal Nathalie, Buckley Christopher D, Luther Sanjiv A (2016), Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation, in Frontiers in immunology, 7, 477-477.
The aged lymphoid tissue environment fails to support naïve T cell homeostasis
Becklund Bryan R, Purton Jared F, Ramsey Chris, Favre Stéphanie, Vogt Tobias K, Martin Christopher E, Spasova Darina S, Sarkisyan Gor, LeRoy Eric, Tan Joyce T, Wahlus Heidi, Bondi-Boyd Brea, Luther Sanjiv A, Surh Charles D (2016), The aged lymphoid tissue environment fails to support naïve T cell homeostasis, in Scientific reports, 6, 30842-30842.
Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells
Korniotis Sarantis, Gras Christophe, Letscher Hélène, Montandon Ruddy, Mégret Jérôme, Siegert Stefanie, Ezine Sophie, Fallon Padraic G, Luther Sanjiv A, Fillatreau Simon, Zavala Flora (2016), Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells, in Nature communications, 7, 12134-12134.

Collaboration

Group / person Country
Types of collaboration
Freddy Radtke/EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Hugh Robson MacDonald/UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Emmanuel Donnadieu/ Institut Cochin in Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Fabienne Tacchini, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Pascal Schneider, Univ. of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dietmar Zehn/UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. C.D.Buckley; MRC Center for Immune regulation, University of Birmingham Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ivan Maillard; Univ. of Michigan United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Daniel Pinschewer; Univ. of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Burkhard Ludewig/ Hospital St.Gallen Switzerland (Europe)
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO conference on ‘Mesenchymal cells in inflammation, immunity and cancer’ Talk given at a conference Interleukin-33 produced by lymph node fibroblasts boosts CD8 T cell responses 19.05.2019 Athens-, Greece Luther Sanjiv;


Self-organised

Title Date Place
Symposium in honor of Dr. Rob MacDonald 12.09.2018 Epalinges, Switzerland

Associated projects

Number Title Start Funding scheme
68805 T zone stromal cells in secondary lymphoid tissues and their roles in providing T cell survival and dendritic cell retention signals 01.08.2003 SNSF Professorships
130488 Fibroblasts of secondary lymphoid organs: central players in tissue homeostasis and immunity 01.05.2010 Project funding (Div. I-III)
185226 Fibroblasts of lymphoid tissues and their role in immunity 01.09.2019 Project funding (Div. I-III)
185226 Fibroblasts of lymphoid tissues and their role in immunity 01.09.2019 Project funding (Div. I-III)
128808 Multicolor flow cytometric analysis of the immune system during homeostasis and activation 01.01.2010 R'EQUIP
160772 The alarmin interleukin-33 in infection, immunity and autoimmunity 01.01.2016 Sinergia
146944 Fibroblasts of secondary lymphoid organs: characterization of their development and function 01.05.2013 Project funding (Div. I-III)

Abstract

1. Summary of the research proposalIt is within the T cell rich zone of secondary lymphoid organs (SLO) that dendritic cells (DC) present the captured pathogens to recirculating T cells in order to activate the rare antigen-specific T cells. This zone is characterized by a sponge-like cellular network made of fibroblasts, called T zone fibroblastic reticular cells (FRC or TRC). Rather than being only structural cells, several laboratories including mine have established important roles for FRC in lymph node (LN) homeostasis and immune response. We could show that FRC not only regulate T cell and DC trafficking by producing CCL19 and CCL21 but also T cell homeostasis by secreting IL-7. More recently, we and others demonstrated a regulatory role for FRC as they attenuated antigen-specific T cell proliferation via nitric oxide production. Despite this recent progress we still have a very incomplete understanding of the development, heterogeneity and function of this ‘novel’ cell type. Over the last twelve years my laboratory has developed the technology and expertise to identify, isolate, culture and characterize FRC at the phenotypic and functional level. We propose to use this expertise to characterize aspects of LN FRC development as well as to identify novel functions in homeostasis, adaptive immunity and tolerance. Aim 1: Defining the immunoregulatory role of FRC in adaptive immunity and tolerance. Aim 2: Investigation of the role of specific molecules present in FRC for their development and function, by using FRC-specific Cre mice crossed to floxed genes of interest.
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