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Imaging-based Systems Biology Analysis of Lymph Node Structure and Function in Viral Infection

Applicant Stein Jens Volker
Number 141918
Funding scheme Sinergia
Research institution Theodor Kocher Institut Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.08.2012 - 31.07.2016
Approved amount 1'400'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (7)

Modelling of immune responses (Systems Biology); Multiphoton microscopy; Optical Projection Tomography ; Lymph node architecture; Viral infection; Adaptive immune response; Lasersheet microscopy (SPIM)

Lay Summary (English)

Lead
Lay summary

Peripheral lymph nodes (PLNs) perform three central functions as a interface between the innate and adaptive immune systems: first, PLNs retain microbes and microbial-derived antigen arriving in lymph, therefore preventing the further spread into surrounding tissue. Second, macrophages and dendritic cells present antigen to passing lymphocytes within PLNs. During inflammation, PLNs typically undergo substantial morphological changes in size, blood and lymph vascularization. As a consequence, the numbers of blood and lymphatic endothelial cells increase to accommodate the increased influx of lymphocytes and influence the outcome of immune responses. Third, the lymphoid tissue regulate the functional outcome of the immune response. Here, we propose to use newly developed rodent models, dynamic imaging of cellular interactions by twophoton microscopy and other imaging methods (Optical projection tomography, OPT and selective plane illumination microscopy, SPIM) to address the role for non-hematopoietic cells during immune responses. Importantly, we will apply a comprehensive systems biology approach for mathematical modelling of high-resolution imaging data and functional analysis of PLN structure and its immunological relevance.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Light sheet fluorescence microscopy for in situ cell interaction analysis in mouse lymph nodes.
Abe Jun, Ozga Aleksandra J, Swoger Jim, Sharpe James, Ripoll Jorge, Stein Jens V (2016), Light sheet fluorescence microscopy for in situ cell interaction analysis in mouse lymph nodes., in Journal of immunological methods, 431, 1-10.
Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.
Zanotti L, Angioni R, Calì B, Soldani C, Ploia C, Moalli F, Gargesha M, D'Amico G, Elliman S, Tedeschi G, Maffioli E, Negri A, Zacchigna S, Sarukhan A, Stein J V, Viola A (2016), Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1., in Leukemia, 30(5), 1143-54.
T Cell Motility as Modulator of Interactions with Dendritic Cells.
Stein Jens V (2016), T Cell Motility as Modulator of Interactions with Dendritic Cells., in Frontiers in immunology, 6, 559-559.
Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality.
Novkovic Mario, Onder Lucas, Cupovic Jovana, Abe Jun, Bomze David, Cremasco Viviana, Scandella Elke, Stein Jens V, Bocharov Gennady, Turley Shannon J, Ludewig Burkhard (2016), Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality., in PLoS biology, 14(7), 1002515-1002515.
WNK1 kinase balances T cell adhesion versus migration in vivo.
Köchl Robert, Thelen Flavian, Vanes Lesley, Brazão Tiago F, Fountain Kathryn, Xie Jian, Huang Chou-Long, Lyck Ruth, Stein Jens V, Tybulewicz Victor L J (2016), WNK1 kinase balances T cell adhesion versus migration in vivo., in Nature immunology, 17(9), 1075-83.
Computational approach to 3D modeling of the lymph node geometry
Kislitsyn R., Savinkov M., Novkovic M., Onder L., Bocharov G. (2015), Computational approach to 3D modeling of the lymph node geometry, in Computation, 3, 222.
In vivo TCR Signaling in CD4(+) T Cells Imprints a Cell-Intrinsic, Transient Low-Motility Pattern Independent of Chemokine Receptor Expression Levels, or Microtubular Network, Integrin, and Protein Kinase C Activity.
Ackerknecht Markus, Hauser Mark A, Legler Daniel F, Stein Jens V (2015), In vivo TCR Signaling in CD4(+) T Cells Imprints a Cell-Intrinsic, Transient Low-Motility Pattern Independent of Chemokine Receptor Expression Levels, or Microtubular Network, Integrin, and Protein Kinase C Activity., in Frontiers in immunology, 6, 297-297.
Intravital and whole-organ imaging reveals capture of melanoma-derived antigen by lymph node subcapsular macrophages leading to widespread deposition on follicular dendritic cells.
Moalli Federica, Proulx Steven T, Schwendener Reto, Detmar Michael, Schlapbach Christoph, Stein Jens V (2015), Intravital and whole-organ imaging reveals capture of melanoma-derived antigen by lymph node subcapsular macrophages leading to widespread deposition on follicular dendritic cells., in Frontiers in immunology, 6, 114-114.
The outer mucus layer hosts a distinct intestinal microbial niche.
Li Hai, Limenitakis Julien P, Fuhrer Tobias, Geuking Markus B, Lawson Melissa A, Wyss Madeleine, Brugiroux Sandrine, Keller Irene, Macpherson Jamie A, Rupp Sandra, Stolp Bettina, Stein Jens V, Stecher Bärbel, Sauer Uwe, McCoy Kathy D, Macpherson Andrew J (2015), The outer mucus layer hosts a distinct intestinal microbial niche., in Nature communications, 6, 8292-8292.
Lymph Node Stromal Cells Negatively Regulate Antigen-Specific CD4(+) T Cell Responses
Abe Jun, Shichino Shigeyuki, Ueha Satoshi, Hashimoto Shin-ichi, Tomura Michio, Inagaki Yutaka, Stein Jens V., Matsushima Kouji (2014), Lymph Node Stromal Cells Negatively Regulate Antigen-Specific CD4(+) T Cell Responses, in JOURNAL OF IMMUNOLOGY, 193(4), 1636-1644.
Lymph Node Stromal Cells Negatively Regulate Antigen-Specific CD4+ T Cell Responses.
Abe Jun, Shichino Shigeyuki, Ueha Satoshi, Hashimoto Shin-Ichi, Tomura Michio, Inagaki Yutaka, Stein Jens V, Matsushima Kouji (2014), Lymph Node Stromal Cells Negatively Regulate Antigen-Specific CD4+ T Cell Responses., in Journal of immunology (Baltimore, Md. : 1950), 193(4), 1636-44.
Mathematical models for CFSE labelled lymphocyte dynamics: asymmetry and time-lag in division
Luzyanina T., Cupovic J., Ludewig B., Bocharov G. (2014), Mathematical models for CFSE labelled lymphocyte dynamics: asymmetry and time-lag in division, in J. Math. Biol., 69(6-7), 1547-1583.
OPTiSPIM: integrating optical projection tomography in light sheet microscopy extends specimen characterization to nonfluorescent contrasts.
Mayer Jürgen, Robert-Moreno Alexandre, Danuser Renzo, Stein Jens V, Sharpe James, Swoger Jim (2014), OPTiSPIM: integrating optical projection tomography in light sheet microscopy extends specimen characterization to nonfluorescent contrasts., in Optics letters, 39(4), 1053-6.
Sensory innervation of the dorsal longitudinal ligament and the meninges in the lumbar spine of the dog.
Waber-Wenger Barbara, Forterre Franck, Kuehni-Boghenbor Kathrin, Danuser Renzo, Stein Jens Volker, Stoffel Michael Hubert (2014), Sensory innervation of the dorsal longitudinal ligament and the meninges in the lumbar spine of the dog., in Histochemistry and cell biology, 100.
The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density
Lee Kit M., Danuser Renzo, Stein Jens V., Graham Delyth, Nibbs Robert J. B., Graham Gerard J. (2014), The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density, in EMBO JOURNAL, 33(21), 2564-2580.
Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4(+) T cell-dendritic cell interactions
Moalli Federica, Cupovic Jovana, Thelen Flavian, Halbherr Pascal, Fukui Yoshinori, Narumiya Shuh, Ludewig Burkhard, Stein Jens V. (2014), Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4(+) T cell-dendritic cell interactions, in JOURNAL OF EXPERIMENTAL MEDICINE, 211(13), 2507-2517.
Endothelial cell-specific lymphotoxin-β receptor signaling is critical for lymph node and high endothelial venule formation.
Onder Lucas, Danuser Renzo, Scandella Elke, Firner Sonja, Chai Qian, Hehlgans Thomas, Stein Jens V, Ludewig Burkhard (2013), Endothelial cell-specific lymphotoxin-β receptor signaling is critical for lymph node and high endothelial venule formation., in The Journal of experimental medicine, 210(3), 465-73.
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.
Mini review: Asymmetry of cell division in CFSE-based lymphocyte proliferation analysis
Bocharov G., Luzyanina T., Cupovic J., Ludewig B. (2013), Mini review: Asymmetry of cell division in CFSE-based lymphocyte proliferation analysis, in Front. Immunol., 4, 264.
Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions.
Coelho Fernanda M, Natale Daniela, Soriano Silvia F, Hons Miroslav, Swoger Jim, Mayer Jürgen, Danuser Renzo, Scandella Elke, Pieczyk Markus, Zerwes Hans-Günter, Junt Tobias, Sailer Andreas W, Ludewig Burkhard, Sharpe James, Figge Marc Thilo, Stein Jens V (2013), Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions., in Blood, 121(20), 4101-9.
A global "imaging" view on systems approaches in immunology
Ludewig B, Stein JV, Sharpe J, Cervantes-Barragan L, Thiel V, Bocharov G (2012), A global "imaging" view on systems approaches in immunology, in European Journal of Immunology, 42(12), 3116-3125.
Quantitative measurements in 3-dimensional datasets of mouse lymph nodes resolve organ-wide functional dependencies.
Mayer Jürgen, Swoger Jim, Ozga Aleksandra J, Stein Jens V, Sharpe James (2012), Quantitative measurements in 3-dimensional datasets of mouse lymph nodes resolve organ-wide functional dependencies., in Computational and mathematical methods in medicine, 2012, 128431-128431.
Fibroblastic reticular cells regulate intestinal inflammation through IL-15-mediated control of group 1 ILCs
Gil-Cruz C., Perez-Shibayama C., Onder L., Chai Q., Cupovic J., Cheng H.-W., Novkovic M., Lang P.A., Geuking M.B., McCoy K.D., Abe S., Cui G., Ikuta K., Scandella E., Ludewig B., Fibroblastic reticular cells regulate intestinal inflammation through IL-15-mediated control of group 1 ILCs, in Nat. Immunol..

Collaboration

Group / person Country
Types of collaboration
Prof. Thomas Hehlgans/University of Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Manolis Pasparakis/University of Cologne Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Tobias Junt, Novartis Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Doron Merkler, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof, Gennady Bocharov Russia (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Ellen Richie, University of Texas United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Ulrich Kalinke/Twincore Hannover Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jorge Ripoll, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Thomas Rülicke, Veterinary University Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Ulf Ahlgren, Umea University Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Tim Sparwasser. Technical University Munich Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Kari Alitalo, University of Helsinki Finland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Mark Coles, University of York Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar Individual talk Imaging the immune system 24.08.2016 Klosterneuburg, Austria Stein Jens Volker;
Seminar Individual talk Imaging the adaptive immune system 06.07.2016 Melbourne, Australia Stein Jens Volker;
SFB T cell immunity Talk given at a conference Imaging the adaptive immune system 09.05.2016 Munich, Germany Stein Jens Volker;
SFB Control-T consortium Talk given at a conference Imaging the adaptive immune system 02.04.2016 Frankfurt, Germany Stein Jens Volker;
Workshop on intravital imaging Talk given at a conference Imaging the adaptive immune system 15.03.2016 Singapore, Singapore Stein Jens Volker;
Seminar Individual talk Imaging the immune system 07.12.2015 University of Strasbourg, France Stein Jens Volker;
Summer School FioCruz Talk given at a conference Imaging the immune system 22.06.2015 Rio de Janeiro, Brazil Stein Jens Volker;
Chemokine conference Talk given at a conference Imaging the Immune system 04.06.2015 Villars-sur-Ollon, Switzerland Ficht Xenia Maria; Stein Jens Volker; Moalli Federica; Matos Coelho Fernanda; Ludewig Burkhard; Ozga Aleksandra;
Imaging the Immune system Individual talk Imaging the Immune system 10.03.2015 Zurich, Switzerland Stein Jens Volker;
Imaging the Immune system Individual talk Imaging the Immune system 02.02.2015 Basel, Switzerland Stein Jens Volker; Ozga Aleksandra;
Hot spring Harbour meeting Individual talk Talk 04.11.2014 Fukuoka, Japan Ficht Xenia Maria; Pieczyk Markus; Stein Jens Volker;
Imaging the Immune system Talk given at a conference Talk 21.10.2014 Milano, Italy Ozga Aleksandra; Stolp Bettina; Pieczyk Markus; Moalli Federica; Stein Jens Volker; Ficht Xenia Maria;
Microscience Microscopy Congress Talk given at a conference SPIM for whole-organ imaging 30.06.2014 Manchester, Great Britain and Northern Ireland Swoger Jim;
European Light Microscopy Initiative Annual Meeting Talk given at a conference SPIM for whole-organ imaging 20.05.2014 Oslo, Norway Swoger Jim;
5th Annual Light Sheet Microscopy Workshop Talk given at a conference SPIM as novel tool for whole-organ analysis 15.09.2013 New York, United States of America Swoger Jim;
European Light Microscopy Initiative (ELMI) meeting Talk given at a conference Leukocyte trafficking 20.05.2013 Arcachon, France, France Sharpe James; Swoger Jim;
Joint Annual Meeting of the Swiss Society for Allergology and Immunology and the Swiss Respiratory Society, Bern Talk given at a conference Leukocyte trafficking 19.04.2013 Bern, CH, Switzerland Stein Jens Volker; Moalli Federica; Pieczyk Markus; Ludewig Burkhard; Chai Qian; Hons Miroslav; Matos Coelho Fernanda; Ozga Aleksandra;
World Immune Regulation Meeting VII Talk given at a conference leukocyte trafficking 13.03.2013 Davos, CH, Switzerland Stein Jens Volker; Matos Coelho Fernanda; Hons Miroslav; Ludewig Burkhard; Pieczyk Markus;
3rd European Congress of Immunology Talk given at a conference leukocyte trafficking 05.09.2012 Glasgow, UK, Great Britain and Northern Ireland Moalli Federica;


Associated projects

Number Title Start Funding scheme
153457 Visualizing molecular mechanisms of organ-specific T cell activation and immune surveillance 01.04.2014 Project funding (Div. I-III)
156234 Expanding live imaging in immunology using high-throughput analysis tools developed in high energy physics 01.11.2014 Interdisciplinary projects
177208 Defining the identity and differentiation pathways of the immune-stimulating fibroblastic tumor stroma 01.01.2018 Sinergia
125447 Examining the function of lymphoid organ structure during antiviral immune responses using microscopic and mesoscopic imaging 01.06.2009 Sinergia
135649 Investigating the molecular factors controlling lymphocyte motility and activation by in vivo imaging 01.04.2011 Project funding (Div. I-III)

Abstract

Peripheral lymph nodes (PLNs) perform three central functions as a structural interface between the innate and adaptive immune systems: first, sentinel PLNs retain microbial-derived antigen (Ag) from the periphery arriving via afferent lymphatic vessels, therefore preventing the further spread into adjacent tissue. Second, macrophages and dendritic cells (DCs), which phagocytose microbial-derived Ag from peripheral sites, present Ag to passing lymphocytes within sentinel PLNs. During inflammation, PLNs typically undergo substantial morphological changes in size, blood and lymph vascularization, cell number and subset composition, and cytokine levels. As a consequence, the numbers of blood and lymphatic endothelial cells, as well as stromal cells of the T cell zone and of B cell follicles increase to accommodate the rising influx of lymphocytes and influence the outcome of immune responses. Third, the lymphoid microenvironment and the T cell - DC interactions regulate the activation or tolerance induction of Ag-specific lymphocytes, as well as the further survival and differentiation of these cells. Here, we propose to use novel stromal mutant mouse models, dynamic in vivo imaging of cellular interactions by twophoton microscopy (2PM) and cutting-edge mesoscopic imaging methods (Optical projection tomography, OPT and selective plane illumination microscopy, SPIM) created during the first Sinergia funding period (2009-2012) to address the role for stromal cells during adaptive and innate immune responses. Importantly, we will apply a comprehensive systems biology approach for mathematical modelling of high-resolution imaging data and functional analysis of PLN structure and its immunological relevance.Our research plan is broken down into three complementary subprojects, which are carried out in a highly synergistic manner by the partners Dr. Stein (UBERN), Prof. Ludewig (KSSG) and Dr. Sharpe (CRG), respectively. The three subprojects address the following aspects of image-based modeling of adaptive immune responses: first, we will integrate innovative imaging developments into the OPTiSPIM hybrid setup - in particular aiming at high-resolution mesoscopic imaging - and transfer SPIM technology from CRG to UBERN. Second, we will analyze the impact of stromal cell-expressed signaling molecules, including the lymphotoxin ß receptor, MyD88 and Interferon A receptor, on the early phase of antiviral immune responses, as well as the functional role of lymphatic vessel restructuring at later phases. In parallel, we will exploit mesoscopic 3D image information to generate high-resolution mathematical models of PLNs during steady state and inflammation. Finally, various models will be integrated for multiscale simulation, which will be completed by tissue-level mathematical modeling of inflammation-induced changes of the PLN architecture. From the sum of our data, we anticipate a synergistic increase in our understanding of antiviral immune responses at an unprecedented level.
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