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Immunology in context: Analyzing adaptive immunity through advanced microscopy

English title Immunology in context: Analyzing adaptive immunity through advanced microscopy
Applicant Stein Jens Volker
Number 172994
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.04.2017 - 31.03.2021
Approved amount 700'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (7)

Twophoton microscopy; Antiviral immune response; Whole-organ 3D imaging; Lymphocyte migration; Immune surveillance; Organ-specific immune surveillance; T cell - DC interactions

Lay Summary (German)

Lead
Das geheime Leben der T-Zellen wird sichtbar
Lay summary
Das erworbene Immunsystem beschützt uns vor Pathogenen, wie beispielsweise viralen Infekten. T-Zellen sind ein wichtiger Bestandteil des erworbenen Immunsystems. Bei einer Infektion werden diese Zellen in Lymphknoten durch sogenannte dendritische Zellen aktiviert und zur Zellteilung angeregt. Die aktivierten T-Zellen strömen nach einigen Tagen aus den Lymphknoten heraus, um in entzündete Gewebe einzudringen und virusinfizierte Zellen zu eliminieren. Mit Hilfe von leistungsstarken Mikroskopen lassen sich nun viele dieser Vorgänge direkt in Mäusen beobachten. Dabei können wir untersuchen, welche Faktoren das molekulare Zwiegespräch von T-Zellen mit dendritischen Zellen beeinflussen und damit die Immunantwort regulieren. Weiterhin untersuchen wir, mit welcher Effizienz aktivierte T-Zellen virusinfizierte Zellen in entzündeten Geweben ausschalten. Damit können wir direkt feststellen, welche Strategien T-Zellen entwickelt haben, um ihr Aufgabe in verschiedenen Organen optimal zu lösen, ohne zu grossen Schaden anzurichten. Unsere Ergebnisse sind für die Erforschung von Autoimmunkrankheiten oder der Effizienz von Krebs-Immunotherapie von Wichtigkeit.
Direct link to Lay Summary Last update: 10.04.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis
Haghayegh Jahromi Neda, Marchetti Luca, Moalli Federica, Duc Donovan, Basso Camilla, Tardent Heidi, Kaba Elisa, Deutsch Urban, Pot Caroline, Sallusto Federica, Stein Jens V., Engelhardt Britta (2020), Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis, in Frontiers in Immunology, 10, 3056.
Vaccination with nanoparticles combined with micro-adjuvants protects against cancer
Mohsen Mona O., Heath Matthew D., Cabral-Miranda Gustavo, Lipp Cyrill, Zeltins Andris, Sande Marcos, Stein Jens V., Riether Carsten, Roesti Elisa, Zha Lisha, Engeroff Paul, El-Turabi Aadil, Kundig Thomas M., Vogel Monique, Skinner Murray A., Speiser Daniel E., Knuth Alexander, Kramer Matthias F., Bachmann Martin F. (2019), Vaccination with nanoparticles combined with micro-adjuvants protects against cancer, in Journal for ImmunoTherapy of Cancer, 7(1), 114-114.
T cells loaded with magnetic nanoparticles are retained in peripheral lymph nodes by the application of a magnetic field
Sanz-Ortega Laura, Rojas José M., Marcos Ana, Portilla Yadileiny, Stein Jens V., Barber Domingo F. (2019), T cells loaded with magnetic nanoparticles are retained in peripheral lymph nodes by the application of a magnetic field, in Journal of Nanobiotechnology, 17(1), 14-14.
Toolbox for In Vivo Imaging of Host–Parasite Interactions at Multiple Scales
De Niz Mariana, Spadin Florentin, Marti Matthias, Stein Jens V., Frenz Martin, Frischknecht Friedrich (2019), Toolbox for In Vivo Imaging of Host–Parasite Interactions at Multiple Scales, in Trends in Parasitology, 35(3), 193-212.
A network of trans-cortical capillaries as mainstay for blood circulation in long bones
Grüneboom Anika, Hawwari Ibrahim, Weidner Daniela, Culemann Stephan, Müller Sylvia, Henneberg Sophie, Brenzel Alexandra, Merz Simon, Bornemann Lea, Zec Kristina, Wuelling Manuela, Kling Lasse, Hasenberg Mike, Voortmann Sylvia, Lang Stefanie, Baum Wolfgang, Ohs Alexandra, Kraff Oliver, Quick Harald H., Jäger Marcus, Landgraeber Stefan, Dudda Marcel, Danuser Renzo, Stein Jens V., et al. (2019), A network of trans-cortical capillaries as mainstay for blood circulation in long bones, in Nature Metabolism, 1(2), 236-250.
Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner
Farsakoglu Yagmur, Palomino-Segura Miguel, Latino Irene, Zanaga Silvia, Chatziandreou Nikolaos, Pizzagalli Diego Ulisse, Rinaldi Andrea, Bolis Marco, Sallusto Federica, Stein Jens V., Gonzalez Santiago F. (2019), Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner, in Cell Reports, 26(9), 2307-2315.e5.
In Vivo Function of the Lipid Raft Protein Flotillin-1 during CD8+ T Cell-Mediated Host Surveillance.
Ficht Xenia, Ruef Nora, Stolp Bettina, Samson Guerric P B, Moalli Federica, Page Nicolas, Merkler Doron, Nichols Ben J, Diz-Muñoz Alba, Legler Daniel F, Niggli Verena, Stein Jens V (2019), In Vivo Function of the Lipid Raft Protein Flotillin-1 during CD8+ T Cell-Mediated Host Surveillance., in The Journal of Immunology, 1900075-1900075.
Initial Viral Inoculum Determines Kinapse-and Synapse-Like T Cell Motility in Reactive Lymph Nodes.
Sivapatham Sujana, Ficht Xenia, Barreto de Albuquerque Juliana, Page Nicolas, Merkler Doron, Stein Jens V (2019), Initial Viral Inoculum Determines Kinapse-and Synapse-Like T Cell Motility in Reactive Lymph Nodes., in Frontiers in Immunology, 10, 2086-2086.
Regulation of global CD8+ T-cell positioning by the actomyosin cytoskeleton.
Stein Jens V, Ruef Nora (2019), Regulation of global CD8+ T-cell positioning by the actomyosin cytoskeleton., in Immunological Reviews, 289, 232-249.
Salivary gland macrophages assist tissue-resident CD8 +T cell immune surveillance
Stolp B, Thelen F, Ficht X, Altenburger L M, Ruef N, Inavalli V V G K, Germann P, Page N, Moalli F, Raimondi A, Keyser K A, Jafari S M Seyed, Barone F, Dettmer M S, Merkler D, Iannacone M, Sharpe J, Schlapbach C, Fackler O T, Nägerl U V, Stein J V (2019), Salivary gland macrophages assist tissue-resident CD8 +T cell immune surveillance, 6, 497-51, BioRxiv, USA 6, 497-51.
VLA-4 mediated adhesion of melanoma cells on the blood–brain barrier is the critical cue for melanoma cell intercalation and barrier disruption
García-Martín Ana B, Zwicky Pascale, Gruber Thomas, Matti Christoph, Moalli Federica, Stein Jens V, Francisco David, Enzmann Gaby, Levesque Mitchell P, Hewer Ekkehard, Lyck Ruth (2019), VLA-4 mediated adhesion of melanoma cells on the blood–brain barrier is the critical cue for melanoma cell intercalation and barrier disruption, in Journal of Cerebral Blood Flow & Metabolism, 51, 1995.
Chemokines and integrins independently tune actin flow and substrate friction during intranodal migration of T cells.
Hons Miroslav, Kopf Aglaja, Hauschild Robert, Leithner Alexander, Gaertner Florian, Abe Jun, Renkawitz Jörg, Stein Jens V, Sixt Michael (2018), Chemokines and integrins independently tune actin flow and substrate friction during intranodal migration of T cells., in Nature Immunology, 19, 606-616.
Fam65b Phosphorylation Relieves Tonic RhoA Inhibition During T Cell Migration
Megrelis Laura, El Ghoul Elyas, Moalli Federica, Versapuech Margaux, Cassim Shamir, Ruef Nora, Stein Jens V, Mangeney Marianne, Delon Jerome (2018), Fam65b Phosphorylation Relieves Tonic RhoA Inhibition During T Cell Migration, in Frontiers in Immunology, 9, 1378-12.
HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface.
Lamas-Murua Miguel, Stolp Bettina, Kaw Sheetal, Thoma Judith, Tsopoulidis Nikolaos, Trautz Birthe, Ambiel Ina, Reif Tatjana, Arora Sakshi, Imle Andrea, Tibroni Nadine, Wu Jingxia, Cui Guoliang, Stein Jens V, Tanaka Motomu, Lyck Ruth, Fackler Oliver T (2018), HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface., in The Journal of Immunology, 201, 2731-2743.
Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice.
Brown M, Assen F P, Leithner A, Abe J, Schachner H, Asfour G, Bago-Horvath Z, Stein J V, Uhrin P, Sixt M, Kerjaschki D (2018), Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice., in Science (New York, NY), 359, 1408-1411.
Preparation of Murine Submandibular Salivary Gland for Upright Intravital Microscopy
Ficht Xenia, Thelen Flavian, Stolp Bettina, Stein Jens V (2018), Preparation of Murine Submandibular Salivary Gland for Upright Intravital Microscopy, in Journal of visualized experiments : JoVE, 1-8.
The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells.
Moalli Federica, Ficht Xenia, Germann Philipp, Vladymyrov Mykhailo, Stolp Bettina, de Vries Ingrid, Lyck Ruth, Balmer Jasmin, Fiocchi Amleto, Kreutzfeldt Mario, Merkler Doron, Iannacone Matteo, Ariga Akitaka, Stoffel Michael H, Sharpe James, Bähler Martin, Sixt Michael, Diz-Muñoz Alba, Stein Jens V (2018), The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells., in Journal of Experimental Medicine, 215, 1869-1890.
A Novel Cervical Spinal Cord Window Preparation Allows for Two-Photon Imaging of T-Cell Interactions with the Cervical Spinal Cord Microvasculature during Experimental Autoimmune Encephalomyelitis
Haghayegh Jahromi Neda, Tardent Heidi, Enzmann Gaby, Deutsch Urban, Kawakami Naoto, Bittner Stefan, Vestweber Dietmar, Zipp Frauke, Stein Jens V, Engelhardt Britta (2017), A Novel Cervical Spinal Cord Window Preparation Allows for Two-Photon Imaging of T-Cell Interactions with the Cervical Spinal Cord Microvasculature during Experimental Autoimmune Encephalomyelitis, in Frontiers in Immunology, 8, 207-18.
Antigen Availability and DOCK2-Driven Motility Govern CD4+ T Cell Interactions with Dendritic Cells In Vivo.
Ackerknecht Markus, Gollmer Kathrin, Germann Philipp, Ficht Xenia, Abe Jun, Fukui Yoshinori, Swoger Jim, Ripoll Jorge, Sharpe James, Stein Jens V (2017), Antigen Availability and DOCK2-Driven Motility Govern CD4+ T Cell Interactions with Dendritic Cells In Vivo., in The Journal of Immunology, 199, 520-530.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Research seminar series Individual talk CD8+ T cell immune surveillance 30.10.2019 Cambridge, Great Britain and Northern Ireland Wissmann Stefanie S; Stein Jens Volker; Altenburger Lukas;
Brazilian Congress of Immunology Talk given at a conference CD8+ T cell immune surveillance 28.09.2019 Florianopolis, Brazil Stein Jens Volker;
Cancer Immunology course Talk given at a conference CD8+ T cell immune surveillance 26.08.2019 Uni Lausanne, Switzerland Stein Jens Volker;
50 year symposium Dept Immunology Uni Zurich Talk given at a conference CD8+ T cell immune surveillance 02.07.2019 Uni Zurich, Switzerland Stein Jens Volker;
ECMC 2019 Talk given at a conference CD8+ T cell immune surveillance 26.06.2019 Salamanca, Spain Stein Jens Volker;
Research seminar series Individual talk CD8+ T cell immune surveillance 30.05.2019 Kyushu, Japan Stein Jens Volker;
Research seminar series Individual talk CD8+ T cell immune surveillance 18.12.2018 Uni Zurich, Switzerland Stein Jens Volker;
Research seminar series Individual talk CD8+ T cell immune surveillance 20.11.2018 Hokkaido, Japan Stein Jens Volker;
Research seminar series Individual talk CD8+ T cell immune surveillance 16.11.2018 Uni Geneva, Switzerland Stein Jens Volker;
Imaging the Immune System Talk given at a conference CD8+ T cell immune surveillance 19.09.2018 Paris, France Stein Jens Volker; Altenburger Lukas; Wissmann Stefanie S;
Gordon Research Conference Talk given at a conference CD8+ T cell immune surveillance 05.06.2018 Newry, United States of America Stein Jens Volker;
From Target to Therapy Talk given at a conference CD8+ T cell immune surveillance 13.04.2018 Würzburg, Germany Stein Jens Volker;
Dendritic cell conference Talk given at a conference DC-triggered CD8+ T cell immune surveillance 18.12.2017 Paris, France Stein Jens Volker;
Cytokine conference Talk given at a conference CD8+ T cell immune surveillance 02.11.2017 Kanazawa, Switzerland Stein Jens Volker;
STIMM seminar series Individual talk CD8+ T cell immune surveillance 07.06.2017 Uni Zurich, Switzerland Stein Jens Volker;
SGAI meeting Talk given at a conference CD8+ T cell immune surveillance 01.06.2017 St. Gallen, Switzerland Thelen Flavian;


Awards

Title Year
AIRC fellowship (Italian Cancer grant) 2019

Associated projects

Number Title Start Funding scheme
170969 Reaction-diffusion networks underlying pattern formation of lymphoid tissue 01.02.2017 Sinergia
153457 Visualizing molecular mechanisms of organ-specific T cell activation and immune surveillance 01.04.2014 Project funding (Div. I-III)
189785 Multichannel confocal microscope with fluorescence lifetime imaging for life science samples 01.03.2020 R'EQUIP
156234 Expanding live imaging in immunology using high-throughput analysis tools developed in high energy physics 01.11.2014 Interdisciplinary projects

Abstract

The adaptive immune system consists of an intricate network of different cell types (CD4+, CD8+ T cells and B cells) and soluble factors that have evolved to provide specific and long-lasting host protection through somatically recombined antigen receptors and long-lived memory cells. T cells express T cell receptors (TCRs) and become activated after binding to peptide-major histocompability complexes (pMHC; “signal 1”) presented on activated antigen-presenting cells (APCs) in lymphoid tissue, in particular dendritic cells (DCs) expressing the costimulatory molecules CD80 and CD86 (“signal 2”). Cytokines such as IL-6, IL12 and IFN? promote further T cell differentiation and expansion (“signal 3”). Decades of in vitro research using cell lines and primary T cells have delineated in great detail the complex membrane-proximal signaling events involving tyrosine kinase activation cascades, phosphoinositde-3-kinase ? (PI3K?) signaling and Ca2+ flux that trigger activation of specific transcription factors. These studies have further uncovered how TCR-triggered signals eventually lead to the initiation of cell cycle progression, metabolic switching and upregulation of effector genes. Activated effector T cells leave secondary lymphoid organs to accumulate in non-lymphoid tissue (NLTs) including skin, mucosal tissues and exocrine glands, where they exert their effector function, e.g. by cytotoxic activity. The recently described tissue-resident memory T cells (TRM) remain after clearance of infection in NLTs as local “first line of defense” and are able to induce an tissue-wide antimicrobial state. Despite this wealth of knowledge, there is only limited information on how these dynamic processes are orchestrated in a spatiotemporal manner in situ and on an organ-wide level, and how the “decision-making” of single T cells during individual interactions with DCs leads to a global scaling of the immune response by integrating signals 1-3. Furthermore, it remains unclear how TRM exert their surveillance task in NLTs, which possess a radically different topology, confinement and barrier properties as compared to lymphoid tissue. Within the last years, we have exploited state-of-the-art twophoton intravital microscopy (2PM) and whole-organ 3D reconstructions to directly visualize and quantify immunologically relevant processes in lymph nodes (LNs) in mouse models. Based on our previous work and the recent commitment of the University of Bern to expand 2PM imaging with new microscope systems, we propose to follow four complementary yet independent research projects. Aim 1. Control of T cell - DC interaction duration and signal integration by a sequestering of a promigratory factor at the immunological synapse. We will examine whether PI3K? activity may function as a “rheostat” to translate TCR signaling strength into prolonged attachment to DCs by sequestering the Rac activator DOCK2 at the immunological synapse, suggesting that late T cell - DC interactions may be controlled by “resistance to T cell-intrinsic detachment”. Aim 2. Real-time “analogue - digital” activation readout using functional reporter T cells. The in-depth signal interaction analysis of T cells interacting with cognate pMHC-presenting DCs require novel tools that reflect the activation status of lymphocytes. We will use recently generated reporter mouse strains of various intracellular parameters to examine signal integration and scaling during T cell priming in LNs by in situ imaging of cellular interactions. Aim 3. CD8+ T cell surveillance of NLTs. Based on our published results on T cell motility and activation, we will examine which molecular and/or biophysical factors determine TRM immune surveillance, using antibody and pharmacological blocking in combination with transgenic mouse models. This will be completed with an assessment of the efficacy of tissue-restricted immunity when challenged. In sum, our data analyze the scaling and surveillance patterns of regulated adaptive immune responses in the context of dynamic in vivo interactions and tissue architecture.
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