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Ontogeny and functional characterization of splenic fibroblastic reticular cells (FRCs) and their mesenchymal precursors during homeostasis and infection

English title Ontogeny and functional characterization of splenic fibroblastic reticular cells (FRCs) and their mesenchymal precursors during homeostasis and infection
Applicant Ludewig Burkhard
Number 159188
Funding scheme Project funding (Div. I-III)
Research institution Institut für Immunbiologie Kantonsspital St. Gallen
Institution of higher education Cantonal hospital of St.Gallen - KSPSG
Main discipline Immunology, Immunopathology
Start/End 01.09.2015 - 31.08.2018
Approved amount 257'267.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Molecular Biology

Keywords (4)

mesenchymal stromal cells; fibroblastic reticular cells; viral infection; spleen

Lay Summary (German)

Lead
Das Ziel dieses Projekts ist die Charakterisierung von mesenchymalen Stromazellen in der Milz und die Bestimmung ihrer Funktion in der Immunhomöostase und Immunaktivierung während viraler Infektionen. Das Projekt ist Teil einer Zusammenarbeit mit Prof. Thomas Hehlgans, Universität Regensburg, Deutschland, und wird über eine D-A-CH Kooperation gefördert.
Lay summary
Sekundäre lymphatische Organe wie die Milz sind kritisch für die Induktion und Aufrechterhaltung von schützenden Immunantworten. Die Organfunktion kann nur wahrgenommen werden, wenn mesenchymale Stromazellen die nötige zelluläre Infrastruktur in definierten Subkompartimenten zur Verfügung stellen können. Das Ziel dieses Projekts ist die Charakterisierung von mesenchymalen Stromazellen in der Milz und die Bestimmung ihrer Funktion in der Immunhomöostase und Immunaktivierung während viraler Infektionen. Zu diesem Zweck wurden neue genetische Modelle entwickelt, die eine zellspezifische und zeitliche Steuerung von Genaktivitäten in mesenchymalen Stromazellen erlauben. Diese Systeme werden eingesetzt, um die Entwicklungsprozesse der Milz im Embryo und in der postnatalen Periode zu untersuchen. Zudem werden Immunprozesse in der Milz von erwachsenen Mäuse untersucht, um die Funktion der mesenchymalen Stromazellen im Verlauf von viralen Infektionen besser zu verstehen. Die Erkenntnisse aus diesen Untersuchungen sind für die Entwicklung von Impfstoffen und die Regulation von überschiessenden Immunantworten von Bedeutung.
Direct link to Lay Summary Last update: 18.08.2015

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Integrative computational modeling of the lymph node stromal cell landscape
NovckovicMario, OnderLucas, ChengHung-Wei, BocharovGennady, Integrative computational modeling of the lymph node stromal cell landscape, in Frontiers in Immunology.

Collaboration

Group / person Country
Types of collaboration
Prof. Robinson/University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Hehlgans/University of Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Rülicke/Veterinary University Vienna Austria (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
World Immune Regulation Meeting XII Poster A two-signal program in myofibroblastic niches controls reticular cell network formation in the splenic white pulp 14.03.2018 Davos, Switzerland Hehlgans Thomas; Ludewig Burkhard; Hung-Wei Cheng;
4th Lymphoid Tissue Meeting Poster Origin and differentiation trajectory of splenic white pulp fibroblastic stromal cells 02.07.2017 St. Gallen, Switzerland Hung-Wei Cheng; Ludewig Burkhard; Hehlgans Thomas;
10th World Immune regulation Meeting Poster Fate mapping of mesenchymal lymphoid tissue organizer cells in the spleen 16.03.2016 Davos, Switzerland Hung-Wei Cheng; Ludewig Burkhard;


Associated projects

Number Title Start Funding scheme
164083 Flow cytometer for multiparametric analysis of rare cell populations 01.12.2015 R'EQUIP
182583 Stromal Cell Niches at the Nexus of the Innate Lymphoid Cell Interactome 01.01.2019 Project funding (Div. I-III)
166500 Defining the origin of lymph node and Peyer's patch fibroblastic reticular cells at single cell resolution 01.04.2016 Project funding (Div. I-III)
177208 Defining the identity and differentiation pathways of the immune-stimulating fibroblastic tumor stroma 01.01.2018 Sinergia

Abstract

Secondary lymphatic organs (SLOs) such as the spleen provide specialized microenvironmental niches for the development and control of immune responses. Particular mesenchymal stromal cells known as fibroblastic reticular cells (FRCs) generate distinct compartments that permit, for example, highly efficient interaction of T cells with dendritic cells. Hence, FRCs are more than simple scaffold-building cells; these cells actively participate in inducing and shaping innate and adaptive immune responses. Our own preliminary data demonstrate that the structure and function of the splenic white pulp exclusively depends on lymphotoxin-beta-receptor (LTbR) signals received by CCL19-positive FRCs during adult life and/or their putative progenitors, i.e. mesenchymal lymphoid tissue organizer cells (mLTOs). In continuation of our existing collaborative activities with Prof. Hehlgans, University of Regensburg, Germany, we have developed a novel inducible lineage-tracing model that permits genetic tagging of splenic FRCs and their progenitors in vivo and will thus facilitate the elucidation of their differentiation pathways throughout spleen development. In addition, this model system provides means for the identification and characterization of molecular mechanisms involved in the maintenance of splenic structure and immune-competence during adult life. Thus, in combination with our already established experimental model of cell type-specific loss of LTbR function, we will be able to resolve the temporal requirement of LTbR signaling for differentiation and function of adult splenic FRCs and their putative progenitors in the embryo. Finally, using an experimental model that facilitates cell type-specific re-activation of LTbR expression in a timely controlled manner, we will test the hypothesis whether FRC-restricted LTbR expression within a specific time window is sufficient for proper white pulp formation and function during embryonic life. Furthermore, we will elucidate the requirements for a timely controlled LTbR activation during adult life in order to maintain compartmentalization and function of the splenic white pulp. Our proposed objectives are based on our individual expertise and present the continuation of our successful collaborative activities. More specifically, they are designed to molecularly characterize splenic FRCs and to dissect lineage-relationship of splenic FRCs with other splenic stromal cells, e.g. their differentiation from mLTO precursors during embryonic development. Moreover, we will be able to identify and functionally characterize the cellular and molecular mechanisms through which LTbR-expressing FRCs are involved in the maintenance of lymphoid organ integrity and immune-competence in the adult spleen, i.e. their ecological role in the splenic micro-environment during immune homeostasis, activation and infection.
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