Modelling of immune responses (Systems Biology); Multiphoton microscopy; Optical Projection Tomography ; Lymph node architecture; Viral infection; Adaptive immune response; Lasersheet microscopy (SPIM)
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.
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.
Stein Jens V (2016), T Cell Motility as Modulator of Interactions with Dendritic Cells., in Frontiers in immunology
, 6, 559-559.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.