Twophoton microscopy; Antiviral immune response; Whole-organ 3D imaging; Lymphocyte migration; Immune surveillance; Organ-specific immune surveillance; T cell - DC interactions
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.
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.
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.
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.
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.
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.
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
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.
Stein Jens V, Ruef Nora (2019), Regulation of global CD8+ T-cell positioning by the actomyosin cytoskeleton., in Immunological Reviews
, 289, 232-249.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.