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Visualizing molecular mechanisms of organ-specific T cell activation and immune surveillance

English title Visualizing molecular mechanisms of organ-specific T cell activation and immune surveillance
Applicant Stein Jens Volker
Number 153457
Funding scheme Project funding (Div. I-III)
Research institution Theodor Kocher Institut Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.04.2014 - 31.03.2017
Approved amount 474'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (7)

Twophoton microscopy; Chemokine receptor signaling ; Lymphocyte migration; Antiviral immune response; Immune surveillance; T cell - DC interactions; Organ-specific immune surveillance

Lay Summary (German)

Lead
Die Lymphozytenmigration während adaptiver Immunantworten
Lay summary

Lymphozyten sind einer der mobilsten Zelltypen und wandern viele hundert Mikrometer in lymphoiden Geweben, wie zum Beispiel Lymphknoten. Mit Hilfe moderner bildgebender Verfahren, vor allem der sogenannten Zweiphotonenmikroskopie, ist es möglich, die Migration und Interaktionen von Lymphozyten mit anderen Zelltypen direkt zu beobachten und zu quantifizieren. Unsere Arbeitsgruppe benutzt diese und andere Techniken, um die Differenzierung von Lymphozyten in Effektorzellen direkt zu untersuchen. Dabei interessieren wir uns vor allem für die Differenzierung von sogenannten follikulären Helferzellen, die eine wichtige unterstützende Rolle bei der Herstellung von schützenden Antikörpern spielen. Durch unsere Forschung erwarten wir, vertiefte Einblicke in diesen Prozess zu gelangen, um dadurch zukünftig verbesserte Impfverfahren zu entwickeln.

Direct link to Lay Summary Last update: 27.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Dynamic intravital imaging of cell-cell interactions in the lymph node.
Stein Jens V, F Gonzalez Santiago (2017), Dynamic intravital imaging of cell-cell interactions in the lymph node., in The Journal of allergy and clinical immunology, 139(1), 12-20.
Real-time tissue offset correction system for intravital multiphoton microscopy.
Vladymyrov Mykhailo, Abe Jun, Moalli Federica, Stein Jens V, Ariga Akitaka (2016), Real-time tissue offset correction system for intravital multiphoton microscopy., in Journal of immunological methods, 438, 35-41.
pMHC affinity controls duration of CD8+ T cell-DC interactions and imprints timing of effector differentiation versus expansion.
Ozga Aleksandra J, Moalli Federica, Abe Jun, Swoger Jim, Sharpe James, Zehn Dietmar, Kreutzfeldt Mario, Merkler Doron, Ripoll Jorge, Stein Jens V (2016), pMHC affinity controls duration of CD8+ T cell-DC interactions and imprints timing of effector differentiation versus expansion., in The Journal of experimental medicine, 213(12), 2811-2829.
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.
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.
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.
T Cell Motility as Modulator of Interactions with Dendritic Cells.
Stein Jens V (2015), T Cell Motility as Modulator of Interactions with Dendritic Cells., in Frontiers in immunology, 6, 559-559.
The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility.
Tang Fengyuan, Gill Jason, Ficht Xenia, Barthlott Thomas, Cornils Hauke, Schmitz-Rohmer Debora, Hynx Debby, Zhou Dawang, Zhang Lei, Xue Gongda, Grzmil Michal, Yang Zhongzhou, Hergovich Alexander, Hollaender Georg A, Stein Jens V, Hemmings Brian A, Matthias Patrick (2015), The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility., in Science signaling, 8(397), 100-100.
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 The Journal of experimental medicine, 211(13), 2507-17.

Collaboration

Group / person Country
Types of collaboration
Prof. Michael Sixt, IST, Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Fukui, Kyushu University Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ludewig/St Gallen Kantonsspital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Doron Merkler, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Sharpe, CRG, Barcelona Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Mario Mellado, CNB, Madrid, Spain Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Thilo Figge, University of Jena Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Adrian Ochsenbein, University of Bern Switzerland (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 Institut Curie Individual talk Analyzing adaptive immunity in rodent models 28.03.2017 Paris, France Ficht Xenia Maria; Stein Jens Volker;
Singapore Winter School of Immunology Talk given at a conference Analyzing adaptive immunity in rodent models 22.01.2017 Singapore, Singapore Thelen Flavian;
Imaging the Immune system Talk given at a conference Analyzing adaptive immunity in rodent models 19.09.2016 Rehovot, Israel Moalli Federica; Stein Jens Volker;
Seminar Monash University Individual talk Analyzing adaptive immunity in rodent models 06.07.2016 Melbourne, Australia Stein Jens Volker;
SGAI meeting Talk given at a conference Analyzing adaptive immunity in rodent models 29.04.2016 Montreux, Switzerland Moalli Federica;
Singapore Biopolis Talk given at a conference Analyzing adaptive immunity in rodent models 15.03.2016 Singapore, Singapore Stein Jens Volker;
Cytomeet Individual talk Analyzing adaptive immunity in rodent models 26.01.2016 Bern, Switzerland Ficht Xenia Maria;
Seminar ISTA Individual talk Analyzing adaptive immunity in rodent models 24.08.2015 Vienna, Austria Stein Jens Volker;
European Chemokine conference Talk given at a conference Analyzing adaptive immunity in rodent models 04.06.2015 Villars-sur-Ollon, Switzerland Moalli Federica; Stein Jens Volker; Thelen Flavian; Ficht Xenia Maria;
Seminar BITG Individual talk Analyzing adaptive immunity in rodent models 16.03.2015 Kreuzlingen, Switzerland Stein Jens Volker;
Seminar ETH Zurich Individual talk Analyzing adaptive immunity in rodent models 10.03.2015 Zurich, Switzerland Stein Jens Volker;


Self-organised

Title Date Place
Cytomeet 2017 29.01.2017 Bern, Switzerland
Cytomeet 2016 18.01.2016 Bern, Switzerland
Cytomeet 2015 23.01.2015 Bern, Switzerland
Imaging the Immune System 23.10.2014 Milan, Italy

Awards

Title Year
Novartis Foundation grant 2016

Associated projects

Number Title Start Funding scheme
141918 Imaging-based Systems Biology Analysis of Lymph Node Structure and Function in Viral Infection 01.08.2012 Sinergia
135649 Investigating the molecular factors controlling lymphocyte motility and activation by in vivo imaging 01.04.2011 Project funding (Div. I-III)
172994 Immunology in context: Analyzing adaptive immunity through advanced microscopy 01.04.2017 Project funding (Div. I-III)

Abstract

Naïve T cells are programmed to home to secondary lymphoid organs (SLOs), including spleen and peripheral lymph nodes (PLNs). There, they scan antigen-presenting cells (APCs), in particular dendritic cells (DCs), for the presence of cognate peptide-MHC (pMHC) complexes. Studies using intravital twophoton microscopy (2PM) of lymphoid tissue in live, anesthetized mice have revealed that interactions are carefully balanced to avoid activation of self-reactive T cells while triggering productive T cell - DC interactions to foreign pMHC. Once naïve T cells become activated, these cells divide and differentiate into effector cells. Some effector cells migrate to the site of inflammation, where a subset of effector memory T cells remains in tissue long after pathogen clearance. These tissue resident memory T cells (TRM) act as first line of defense upon pathogen re-exposure. On the other hand, follicular helper T cells (TFH) remain in lymphoid organs to provide B cell help in germinal centers and ensure the generation of high-affinity mAbs for protective immunity. In sum, a defining feature of T cells is their capacity to migrate through blood and lymph to lymphoid and non-lymphoid organs, where they engage in dynamic interactions with other hematopoietic and stromal cells. Here, we propose to use mouse models for the functional visualization of interactions of T cells, APCs and stromal cells in lymphoid and non-lymphoid organs during acute and memory responses, in sterile and infectious inflammation. We will carry out four complementary projects. First, we will perform an in-depth 2PM analysis of lymphoid stroma - T cell interactions for efficient motility. Second, we will use functional 2PM imaging of signaling reporters to visualize checkpoints of TFH formation and compare these with a mutant strain with impaired TFH formation, using gene expression analysis and 2PM. We will also examine the effect of HIV-1 pathogenicity factor Nef for TFH function Third, we will investigate CD8+ T cell activation with cognate and altered peptide ligands and examine their impact on encounters with DCs arriving later during immune responses using flow cytometry and 2PM. The fourth and major part focuses on the role of intracellular and extracellular signaling molecules governing T cell immune surveillance through stromal cell and APC interactions in steady state, as well as during acute and memory phase of virus infections. Our model organs are PLNs for central memory T cells, as well as salivary gland and skin for effector memory T cells. Using transgenic mouse models and pharmacological inhibitors, which interfere with distinct key intracellular factors of the small GTPases family and integrins, we will make an in-depth 2PM and flow cytometry analysis of organ-specific migration requirements. An important part of this aim is to assign site-specific roles for signaling modules to efficient motility in tissues with increasing epithelial content (“tissue density”) and to correlate our findings with resolution of antimicrobial infection. In sum, our proposal builds on our established line of research of visualizing immune responses, while taking into account infectious models and the tissue context of immune surveillance.
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