Project

Back to overview

Fibroblasts of secondary lymphoid organs: central players in tissue homeostasis and immunity

English title Fibroblasts of secondary lymphoid organs: central players in tissue homeostasis and immunity
Applicant Luther Sanjiv
Number 130488
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 01.05.2010 - 30.04.2013
Approved amount 468'000.00
Show all

Keywords (12)

stromal cells; lymph node; T cell homeostasis; T cell activation; Secondary lymphoid tissues; architecture; homeostasis; inflammation; dendritic cell function; chemokines; cytokines; extracellular matrix

Lay Summary (English)

Lead
Lay summary
Secondary lymphoid tissues, such as lymph nodes and spleen, are critical for the efficient activation of lymphocytes. While we have made considerable progress in understanding the biology of lymphocytes that recirculate through these organs, we know very little about the resident cells that form the 'niches' within this unique microenvironment. It has been recently discovered that stromal cell networks within these secondary lymphoid tissues not only serve as support structure, but actively control lymphocyte and dendritic cell migration and positioning by secreting chemotactic factors.Stromal cells found within the T zone have been mainly characterized morphologically. They display fibroblast like morphology and associate with extracellular matrix fibres. A more active function was suggested by our finding that T zone stromal cells are the major constitutive source of the chemokines CCL19 and CCL21 that promote the attraction of CCR7-bearing dendritic cells and T cells. We propose that resident T zone stromal cells are ideally positioned not only to attract T cells and dendritic cells into their proximity but also to influence their survival, interaction, proliferation and differentiation. To study T zone stromal cells in mice we have developed several novel tools, including isolation and staining protocols, in vitro assays, immortalized cell lines, 3D culture systems and transgenic mouse models. They are currently used to address the following aspects of T zone stromal cells:1) their phenotype (incl. transcriptional profiling) during homeostasis and immune response2) their function in T cell and dendritic cell homeostasis3) their function in T cell activation4) their development in neonatal tissues and at sites of inflammationWhile most experiments will be done using murine tissues we have recently validated that highly similar stromal cells also exist in human tissues. A better understanding of these stromal cells should help to design strategies to target the stromal cell compartment during pathogenesis, by either boosting it during infection, or by interfering with it in the case of autoimmune disease. A particular attractive target are sites of chronic inflammation where interference with stromal cell development should by highly beneficial.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
Interstitial dendritic cell guidance by haptotactic chemokine gradients.
Weber Michele, Hauschild Robert, Schwarz Jan, Moussion Christine, de Vries Ingrid, Legler Daniel F, Luther Sanjiv A, Bollenbach Tobias, Sixt Michael (2013), Interstitial dendritic cell guidance by haptotactic chemokine gradients., in Science (New York, N.Y.), 339(6117), 328-32.
Positive and negative regulation of T cell responses by fibroblastic reticular cells within paracortical regions of lymph nodes.
Siegert Stefanie, Luther Sanjiv A (2012), Positive and negative regulation of T cell responses by fibroblastic reticular cells within paracortical regions of lymph nodes., in Frontiers in immunology, 3, 285-285.
Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells.
Matter Matthias S, Hilmenyuk Tamara, Claus Christina, Marone Romina, Schürch Christian, Tinguely Marianne, Terracciano Luigi, Luther Sanjiv A, Ochsenbein Adrian F (2011), Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells., in PloS one, 6(9), e24772-1-e24772-13.
Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide.
Siegert Stefanie, Huang Hsin-Ying, Yang Chen-Ying, Scarpellino Leonardo, Carrie Lucie, Essex Sarah, Nelson Peter J, Heikenwalder Matthias, Acha-Orbea Hans, Buckley Christopher D, Marsland Benjamin J, Zehn Dietmar, Luther Sanjiv A (2011), Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide., in PloS one, 6(11), e27618-1-e27618-14.
Guiding blind T cells and dendritic cells: A closer look at fibroblastic reticular cells found within lymph node T zones.
Luther Sanjiv A, Vogt Tobias K, Siegert Stefanie (2011), Guiding blind T cells and dendritic cells: A closer look at fibroblastic reticular cells found within lymph node T zones., in Immunology letters, 138(1), 9-11.
Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans
Link A, Hardie DL, Favre S, Britschgi MR, Adams DH, Sixt M, Cyster JG, Buckley CD, Luther SA (2011), Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans, in AMERICAN JOURNAL OF PATHOLOGY, 178(4), 1662-1675.
Expression and function of interleukin-7 in secondary and tertiary lymphoid organs.
Huang Hsin-Ying, Luther Sanjiv A, Expression and function of interleukin-7 in secondary and tertiary lymphoid organs., in Seminars in immunology.
Innate Signalling 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, Innate Signalling Promotes Formation of Regulatory Nitric Oxide-Producing Dendritic Cells Limiting T Cell Expansion in Experimental Autoimmune Myocarditis., in Circulation.

Collaboration

Group / person Country
Types of collaboration
Hospital of St.Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Technical University of Munich Germany (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
Research seminar 18.01.2013 CMU, Genève
American College of Rheumatology Annual Meeting 09.11.2012 Washington DC, USA
Gordon conference in Immunochemistry and Immunobiology. 10.06.2012 Les Diablerets, Switzerland
Annual European Congress of Rheumatology 06.06.2012 Berlin
Research seminar at the University of Bern (Dep. of Pharmacology) 18.01.2012 Bern
Annual conference of the British Society of Immunology 05.12.2011 Liverpool, England
Germinal center conference 04.09.2011 Birmingham, England
Research seminar 12.07.2011 INSERM Lyon, France
4th International Symposium of the SFB621 on ‘Pathobiology of the Intestinal Mucosa 27.05.2011 Hannover, Germany
Research seminar 17.05.2011 ETH Zurich


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Inauguration du centre Leenaards de la mémoire 11.03.2013 CHUV, Lausanne, Switzerland


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Ceremony for Leenaards Price Western Switzerland 29.03.2012
Media relations: print media, online media Press conference for Leenaards Price Zeitungen, Radio Western Switzerland 20.03.2012

Awards

Title Year
Poster price 2013
Price of the Leenaards Foundation 2012
Teaching grant, Univ. of Lausanne 2011

Associated projects

Number Title Start Funding scheme
166161 Fibroblasts of lymphoid tissues: from phenotype to function 01.05.2016 Project funding (Div. I-III)
128808 Multicolor flow cytometric analysis of the immune system during homeostasis and activation 01.01.2010 R'EQUIP
146944 Fibroblasts of secondary lymphoid organs: characterization of their development and function 01.05.2013 Project funding (Div. I-III)
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
116896 T zone stromal cells in secondary lymphoid tissues and their roles in dendritic cell retention and T cell homeostasis 01.08.2007 SNSF Professorships

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. While we have made considerable progress in understanding the biology of DC and T lymphocytes, we know very little about the reticular stromal cells that form the ‘niches’ within the T zone. T zone fibroblastic reticular cells (TRC) were recently shown to produce a sponge-like cellular network that serves as a ‘road system’ for migrating lymphocytes. Over the last six years my laboratory has developed the technology to isolate, culture and characterize stromal cells of the T zone at the phenotypic and functional level. We could demonstrate that these TRC are a distinct mesenchymal cell type with active functions for the adaptive immune system, as they control the size of the peripheral T cell pool and the encounters with DC. My laboratory is now in an excellent position to further dissect the phenotype, regulation and function of these poorly characterized TRC. Therefore, our four major aims focus on improving our understanding of the role of the T zone microenvironment and TRC in particular for the homeostasis and activation of the adaptive immune system. Aim 1: Cells and signals regulating TRC homeostasis and IL-7 expression in lymph nodesThe number of TRC and their IL-7 expression level must be strictly regulated as together they control the size of the peripheral T cell pool. We wish to gain insight into this regulation by investigating the role of lymphocytes, DC and cytokines in this process.Aim 2: In vitro characterization of the role of TRC for T cell activationTo be able to study TRC regulation and function in a highly accessible system, we have established B6 TRC lines that we can coculture with antigen-presenting DC and T cells. As we have observed that TRC initially delay T cell activation, we aim to establish whether this effect is TRC-specific and identify the mechanism and molecules involved. Aim 3: Characterization of the TRC reaction during immune response and LN swelling Preliminary results suggest that TRC numbers strongly increase during LN swelling, concordant with the increase in T cell numbers. We plan to characterize the phenotype, number, turnover and organization of TRC during the course of the immune response and investigate the cells and factors involved. Another focus will be to identify novel functions of activated versus naïve TRC by looking at the transcriptional profile.
-