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Fibroblasts of secondary lymphoid organs: characterization of their development and function

English title Fibroblasts in secondary lymphoid organs: characterization of their development and function
Applicant Luther Sanjiv
Number 146944
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 01.05.2013 - 30.04.2016
Approved amount 493'920.00
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Keywords (4)

lymph node; T cell activation; fibroblastic reticular cells; immune regulation

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 und dendritische Zellen funktionieren. Noch relativ wenig erforscht sind die nicht-hematopoietischen Zellen in diesen Organen, inklusive Blut- und Lymphgefässe so wie auch die verschiedenen Fibroblasten.
Lay summary

Dieses Projekt zielt auf eine bessere phenotypische und funktionelle Charakterisierung der Fibroblasten im Lymphknoten der Maus ab. 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 karaktersiert, 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) Welche unterschiedlichen Fibroblasten-Typen gibt es und was ist ihre Funktion?

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

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

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: 30.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
CD8 engineered cytotoxic T cells reprogram melanoma tumor environment
Leignadier Julie, Favre Stephanie, Luther Sanjiv A., Luescher Immanuel F. (2015), CD8 engineered cytotoxic T cells reprogram melanoma tumor environment, in OncoImmunology, 5(3), e1086861-e1086861.
DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport
Bernier-Latmani Jeremiah, Cisarovsky Christophe, Demir Cansaran Saygili, Bruand Marine, Jaquet Muriel, Davanture Suzel, Ragusa Simone, Siegert Stefanie, Dormond Olivier, Benedito Rui, Radtke Freddy, Luther Sanjiv A., Petrova Tatiana V. (2015), DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport, in Journal of Clinical Investigation, 125(12), 4572-4586.
IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs
Barone Francesca, Nayar Saba, Campos Joana, Cloake Thomas, Withers David R., Toellner Kai-Michael, Zhang Yang, Fouser Lynette, Fisher Benjamin, Bowman Simon, Rangel-Moreno Javier, Garcia-Hernandez Maria de la Luz, Randall Troy D., Lucchesi Davide, Bombardieri Michele, Pitzalis Costantino, Luther Sanjiv A., Buckley Christopher D. (2015), IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs, in Proceedings of the National Academy of Sciences, 112(35), 11024-11029.
Conditional Deletion of Ferritin H in Mice Reduces B and T Lymphocyte Populations
Vanoaica Liviu, Richman Larry, Jaworski Maike, Darshan Deepak, Luther Sanjiv A., Kühn Lukas C. (2014), Conditional Deletion of Ferritin H in Mice Reduces B and T Lymphocyte Populations, in PLoS ONE, 9(2), e89270-e89270.
Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity
Jaworski M., Marsland B. J., Gehrig J., Held W., Favre S., Luther S. A., Perroud M., Golshayan D., Gaide O., Thome M. (2014), Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity, in The EMBO Journal, 33(23), 2765-2781.
Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses.
Fasnacht Nicolas, Huang Hsin-Ying, Koch Ute, Favre Stéphanie, Auderset Floriane, Chai Qian, Onder Lucas, Kallert Sandra, Pinschewer Daniel D, MacDonald H Robson, Tacchini-Cottier Fabienne, Ludewig Burkhard, Luther Sanjiv A, Radtke Freddy (2014), Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses., in The Journal of experimental medicine, 211(11), 2265-79.
Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes.
Yang Chen-Ying, Vogt Tobias K, Favre Stéphanie, Scarpellino Leonardo, Huang Hsin-Ying, Tacchini-Cottier Fabienne, Luther Sanjiv A (2014), Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes., in Proceedings of the National Academy of Sciences of the United States of America, 111(1), 109-18.
DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells
Ferrero Isabel, Koch Ute, Claudinot Stephanie, Favre Stéphanie, Radtke Freddy, Luther Sanjiv A., MacDonald H. R. (2013), DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells, in European Journal of Immunology, 43(11), 2845-2853.
Inducible gene expression in fetal thymic epithelium: A new BAC transgenic modelInducible Gene Expression in Fetal TECs
Fiorini Emma, Ferrero Isabel, Poisson Caroline, Scarpellino Leonardo, Luther Sanjiv Andreas, MacDonald H. Robson (2013), Inducible gene expression in fetal thymic epithelium: A new BAC transgenic modelInducible Gene Expression in Fetal TECs, in genesis, 51(10), 717-724.
Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis.
Kania Gabriela, Siegert Stefanie, Behnke Silvia, Prados-Rosales Rafael, Casadevall Arturo, Lüscher Thomas F, Luther Sanjiv A, Kopf Manfred, Eriksson Urs, Blyszczuk Przemyslaw (2013), Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis., in Circulation, 127(23), 2285-94.
Interstitial Dendritic Cell Guidance by Haptotactic Chemokine Gradients
Weber M., Hauschild R., Schwarz J., Moussion C., de Vries I., Legler D. F., Luther S. A., Bollenbach T., Sixt M. (2013), Interstitial Dendritic Cell Guidance by Haptotactic Chemokine Gradients, in Science, 339(6117), 328-332.
Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.
Chai Qian, Onder Lucas, Scandella Elke, Gil-Cruz Cristina, Perez-Shibayama Christian, Cupovic Jovana, Danuser Renzo, Sparwasser Tim, Luther Sanjiv A, Thiel Volker, Rülicke Thomas, Stein Jens V, Hehlgans Thomas, Ludewig Burkhard (2013), Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity., in Immunity, 38(5), 1013-24.
Notch signaling regulates follicular helper T cell differentiation.
Auderset Floriane, Schuster Steffen, Fasnacht Nicolas, Coutaz Manuel, Charmoy Mélanie, Koch Ute, Favre Stéphanie, Wilson Anne, Trottein François, Alexander James, Luther Sanjiv A, MacDonald H Robson, Radtke Freddy, Tacchini-Cottier Fabienne (2013), Notch signaling regulates follicular helper T cell differentiation., in Journal of immunology (Baltimore, Md. : 1950), 191(5), 2344-50.

Collaboration

Group / person Country
Types of collaboration
Hugh Robson MacDonald/UNIL 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
Chris 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
- Exchange of personnel
Ivan Maillard, Univ. Michigan United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Fabienne Tacchini, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Burkhard Ludewig/ Hospital St.Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Emmanuel Donnadieu/ Institut Cochin in Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Freddy Radtke/EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual conference of the Swiss Society of Allergy and Immunology Talk given at a conference 2 posters: 1 by One phD student (F. Renevey) and a short talk by K. Schäuble 28.04.2016 Montreux, Switzerland Schäuble Karin; Luther Sanjiv;
Keystone Conference on "Stromal cells in immunity" Talk given at a conference Short Talk: Identification of a New Fibroblast Subset Forming Plasma Cell Survival Niches in Activated Lymph Nodes + + poster by one lab member: H.-Y. Huang 08.02.2016 Keystone, United States of America Luther Sanjiv;
First European Chemokine and Cell Migration Conference Talk given at a conference Chemokines and fibroblastic reticular cells as regulators of lymph node niche 06.06.2015 Villars, Switzerland Luther Sanjiv;
Annual Conference of the Swiss Society of Allergy and Immunology (SSAI) Poster http://ssai.ch/index.php?id=240&L=2 12.02.2015 Basel, Switzerland Luther Sanjiv; Schäuble Karin;
Inbionet Lausanne Workshop (Marie Curie Network) Talk given at a conference Workshop Seminar: The role of Fibroblastic reticular cells in regulating immune responses 13.06.2014 EPFL, Lausanne, Switzerland Luther Sanjiv;
3rd international lymphoid tissue meeting Talk given at a conference Lymph node fibroblasts: behavior and function during adaptive immunity+ 2 posters by lab members: C.Y. Yang, and H.-Y. Huang 15.09.2013 Rotterdam, Netherlands Luther Sanjiv;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
JOM (journée oser les métier) La biologie des tissues et cellules Talk 12.11.2015 Epalinges, Switzerland Luther Sanjiv;
JOM (journée oser les métier) Workshop 14.11.2013 Epalinges, Switzerland Favre Stéphanie; Luther Sanjiv;


Awards

Title Year
Price for best poster in fundamental immunology (at the swiss conference for immunology and allergology) 2017
Poster Price at the Annual Conference of Swiss Society of Allergy and Immunology for my PhD student C.-Y. Yang 2013

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
166161 Fibroblasts of lymphoid tissues: from phenotype to function 01.05.2016 Project funding (Div. I-III)
130488 Fibroblasts of secondary lymphoid organs: central players in tissue homeostasis and immunity 01.05.2010 Project funding (Div. I-III)
150799 Advanced analysis of the function of single cells using flow imaging. 01.12.2013 R'EQUIP
128808 Multicolor flow cytometric analysis of the immune system during homeostasis and activation 01.01.2010 R'EQUIP

Abstract

It 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, hetereogeneity and function of this ‘novel’ cell type. Over the last nine 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: Characterization of FRC heterogeneity in murine lymph nodes going from phenotype to functionAim 2: Defining the immunoregulatory role of FRC in adaptive immunity and toleranceAim 3: Use of Cre-lox technology to study FRC development and function
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