SFB 704:  Molecular Mechanisms and Chemical Modulation of Local Immune Regulation

• Subject Area: Biology ; Chemistry ; Medicine
• Term: from 2006 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 15477770

• Final Report Year: 2018

Final Report Abstract

Local control of immunity is required to cope with specialized pathogens, which attempt to break barriers via their preferred entry routes, but it is also needed for the maintenance of organ integrity. For example, activation of immunity in the brain is by no means adapted to allow similar dramatic consequences as analogous immune reactions in barrier organs - such as the skin - might have, because of the vastly different potentials of these tissues for repair, or their strongly divergent requirements for cellular integrity as a basis for continuous organ function. Our research initiative CRC 704 thus had aimed at the analysis and classification of cell types and their modes of interaction in the local control of immunity, tolerance and homeostasis. We further investigated into signaling circuits and transcriptional networks, to be able to better understand and eventually manipulate these systems in clinically relevant situations. We finally incorporated modern chemistry to generate small organic compounds or nucleic-acid based chemical tools to complement the main experimental tools (mouse genetics, cellular and molecular immunology, biochemistry) with novel investigative molecules that may be employed in a more quantitative fashion, and which successfully serve as leads for clinical developments.

Publications

• (2006). Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature 444, 941-4
  Hafner, M., Schmitz, A., Grüne, I.,Srivatsan, S.G.,Paul, B., Kolanus, W., Quast, T., Kremmer, E., Bauer, I., Famulok, M.
  (See online at https://doi.org/10.1038/nature05415)
• (2006). The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature 444, 945-8
  Fuss, B., Becker, T., Zinke, I., Hoch, M.
  (See online at https://doi.org/10.1038/nature05412)
• (2008). 5'-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat Med 14, 1256-63
  Poeck, H., Besch, R., Maihoefer, C., Renn, M., Tormo, D., Morskaya, S.S., Kirschnek, S., Gaffal, E., Landsberg, J., Hellmuth, J., Schmidt, A., Anz, D., Bscheider, M., Schwerd, T., Berking, C., Bourquin, C., Kalinke, U., Kremmer, E., Kato, H., Akira, S., Meyers, R., Hacker, G., Neuenhahn, M., Busch, D., Ruland, J., Rothenfusser, S., Prinz, M., Hornung, V., Endres, S., Tuting, T. and Hartmann, G.
  (See online at https://doi.org/10.1038/nm.1887)
• (2008). Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation. Nat Immunol 9, 558-566
  Burgdorf, S., Schölz, C., Kautz, A., Tampé, R. and Kurts, C.
  (See online at https://doi.org/10.1038/ni.1601)
• (2009). Cytohesin-1 controls the activation of RhoA and modulates integrin-dependent adhesion and migration of dendritic cells. Blood 113, 5801–5810
  Quast, T., Tappertzhofen, B., Schild, C., Grell, J., Czeloth, N., Förster, R., Alon, R., Fraemohs, L., Dreck, K., Weber, C., Lämmermann, T., Sixt, M. and Kolanus, W.
  (See online at https://doi.org/10.1182/blood-2008-08-176123)
• (2010). A cytohesin homolog in Dictyostelium amoebae. PLoS One 5(2):e9378
  Shina, M.C., Müller, R., Blau-Wasser, R., Glöckner, G., Schleicher, M., Eichinger, L., Noegel, A.A. and Kolanus, W.
  (See online at https://doi.org/10.1371/journal.pone.0009378)
• (2010). Alternative cross-priming through CCL17/CCR4-mediated CTL attraction towards NKT cell-licensed dendritic cells. Nat. Immunol. 11, 313-320
  Semmling, V., Lukacs-Kornek, V., Thaiss, C., Quast, T., Hochheiser, K., Panzer, U., Rossjohn, J., Perlmutter, P., Cao, J., Godfrey, D., Savage, P., Knolle, P., Kolanus, W., Förster, I. and Kurts, C.
  (See online at https://doi.org/10.1038/ni.1848)
• (2010). FOXO-dependent regulation of innate immune homeostasis. Nature 463, 369-73
  Becker, T., Loch, G., Beyer, M., Zinke, I., Aschenbrenner, A.C., Carrera, P., Inhester, T., Schultze, J.L., Hoch, M.
  (See online at https://doi.org/10.1038/nature08698)
• (2010). Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol 11, 63-9
  Poeck, H., Bscheider, M., Gross, O., Finger, K., Roth, S., Rebsamen, M., Hannesschläger, N., Schlee, M., Rothenfusser, S., Barchet, W., Kato, H., Akira, S., Inoue, S., Endres, S., Peschel, C., Hartmann, G., Hornung, V. and Ruland, J.
  (See online at https://doi.org/10.1038/ni.1824)
• (2010). Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells. Proc. Natl. Acad. Sci. USA 107, 8736-8741
  Stutte, S., Quast, T., Gerbitzki, N., Savinko, T., Novak, N., Reifenberger, J., Homey, B., Kolanus, W., Alenius, H. and Förster, I.
  (See online at https://doi.org/10.1073/pnas.0906126107)
• (2010). Virtual screening identifies structurally diverse cytohesin inhibitors with differentiated biological functions. ACS Chem. Biol. 5, 839-849
  Stumpfe, D., Bill, A., Novak, N., Loch, G., Blockus, H., Geppert, H., Becker, T., Schmitz, A., Hoch, M., Kolanus, W., Famulok, M. and Bajorath, J.
  (See online at https://doi.org/10.1021/cb100171c)
• (2011). Regulation of dectin-1-mediated dendritic cell activation by peroxisome proliferator-activated receptor-gamma ligand troglitazone. Blood 17, 3569-3574
  Kock, G., Bringmann, A., Held, S.A., Daecke, S., Heine, A. and Brossart, P.
  (See online at https://doi.org/10.1182/blood-2010-08-302224)
• (2011). Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol. 12, 898-907
  Beyer, M., Thabet, Y., Müller, R.U., Sadlon, T., Classen, S., Lahl, K., Basu, S., Zhou X., Bailey- Bucktrout, S.L., Krebs, W., Schönfeld, E.A., Böttcher, J., Golovina, T., Mayer, C.T., Hofmann, A., Sommer, D., Debey-Pascher, S., Endl, E., Limmer, A., Hippen, K.L., Blazar, B.R., Balderas, R., Quast, T., Waha, A., Mayer, G., Famulok, M., Knolle, P.A., Wickenhauser, C., Kolanus, W., Schermer, B., Bluestone, J.A., Barry, S.C., Sparwasser, T., Riley J.L. and Schultze, J.L.
  (See online at https://doi.org/10.1038/ni.2084)
• (2012). Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412-416
  Landsberg, J., Kohlmeyer, J., Renn, M., Bald, T., Rogava, M., Cron, M., Fatho, M., Lennerz, V., Wölfel, T., Hölzel, H. and Tüting, T.
  (See online at https://doi.org/10.1038/nature11538)
• (2013). Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase. Cell 153, 1094–1107
  Gao, P., Ascano, M., Wu, Y., Barchet, W., Gaffney, B.L., Zillinger, T., Serganov, A.A., Liu, Y., Jones, R.A., Hartmann, G., Tuschl, T. and Patel, D.J.
  (See online at https://doi.org/10.1016/j.cell.2013.04.046)
• (2013). Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 14, 574-583
  Huang, L.R., Wohlleber, D., Reisinger, F., Jenne, C.N., Cheng, R.L., Abdullah, Z., Schildberg, F.A., Odenthal, M., Dienes, H.P., van Rooijen, N., Schmitt, E., Garbi, N., Croft, M., Kurts, C., Kubes, P., Protzer, U., Heikenwalder, M. and Knolle, P.A.
  (See online at https://doi.org/10.1038/ni.2573)
• (2013). Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Antiinfectious Immunity. Cell Reports 3, 779-795
  Böttcher, J.P., Schanz, O., Wohlleber, D., Abdullah, Z., Debey-Pascher, S., Staratschek-Jox, A., Hochst, B., Hegenbarth, S., Grell, J., Limmer, A., Atreya, I., Neurath, M.F., Busch, D.H., Schmitt, E., van Endert, P., Kolanus, W., Kurts, C., Schultze, J.L., Diehl, L. and Knolle, P.A.
  (See online at https://doi.org/10.1016/j.celrep.2013.02.008)
• (2013). Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482-495
  Gehrke, N., Mertens, C., Zillinger, T., Wenzel, J., Bald, T., Zahn, S., Tüting, T., Hartmann, G. and Barchet, W.
  (See online at https://doi.org/10.1016/j.immuni.2013.08.004)
• (2013). RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J Exp Med. 21; 2447-63
  Sirois, C.M., Jin, T., Miller, A.L., Bertheloot, D., Nakamura, H., Horvath, G.L., Mian, A.,Jiang, J., Schrum, J., Bossaller, L., Pelka, K., Garbi, N., Brewah, Y., Tian, J., Chang, C., Chowdhury, P.S., Sims, G.P., Kolbeck, R., Coyle, A.J., Humbles, A.A., Xiao, T.S. and Latz, E.
  (See online at https://doi.org/10.1084/jem.20120201)
• (2013). Structure-Function Analysis of STING Activation by c[G(2′,5′)pA(3′,5′)p] and Targeting by Antiviral DMXAA. Cell 154, 748–762
  Gao, P., Ascano, M., Zillinger, T., Wang, W., Dai, P., Serganov, A.A., Gaffney, B.L., Shuman, S., Jones, R.A., Deng, L., Hartmann, G., Barchet, W., Tuschl, T., and Patel, D.J.
  (See online at https://doi.org/10.1016/j.cell.2013.07.023)
• (2014). Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156, 456-468
  Schiwon, M., Weisheit, C., Franken, L., Gutweiler, S., Dixit, A., Meyer-Schwesinger, C., Pohl, J.M., Maurice, N.J., Thiebes, S., Lorenz, K., Quast, T., Fuhrmann, M., Baumgarten, G., Lohse, M.J., Opdenakker, G., Bernhagen, J., Bucala, R., Panzer, U., Kolanus, W., Gröne, H.J., Garbi, N., Kastenmüller, W., Knolle, P.A., Kurts, C. and Engel, D.R.
  (See online at https://doi.org/10.1016/j.cell.2014.01.006)
• (2014). Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci. 34, 8546-56
  Bodea, L.G., Wang, Y., Linnartz-Gerlach, B., Kopatz, J., Sinkkonen, L., Musgrove, R., Kaoma, T., Muller, A., Vallar, L., Di Monte, D.A., Balling, R. and Neumann, H.
  (See online at https://doi.org/10.1523/jneurosci.5002-13.2014)
• (2014). Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274-88
  Xue, J., Schmidt, S.V., Sander, J. Draffehn, A., Krebs, W., Quester, I., De Nardo, D., Gohel, T.D., Emde, M., Schmidleithner, L., Ganesan, H., Nino-Castro, A., Mallmann, M.R., Labzin, L., Theis, H., Kraut, M., Beyer, M., Latz, E., Freeman, T.C., Ulas, T. and Schultze, J.L.
  (See online at https://doi.org/10.1016/j.immuni.2014.01.006)
• (2014). Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109-113
  Bald, T., Quast, T., Landsberg, J., Rogava, M., Glodde, N., Lopez-Ramos, D., Kohlmeyer, J., Riesenberg, S., van den Boorn-Konijnenberg, D., Hömig-Hölzel, C., Reuten, R., Schadow, B., Weighardt, H., Wenzel, D., Helfrich, I., Schadendorf, D., Bloch, W., Bianchi, M.E., Lugassy, C., Barnhill, R.L., Koch, M., Fleischmann, B.K., Förster, I., Kastenmüller, W., Kolanus, W., Hölzel, M., Gaffal E. and Tüting, T.
  (See online at https://doi.org/10.1038/nature13111)
• (2015). Functional classification of memory CD8(+) T cells by CX3CR1 expression. Nat. Commun. 6, 8306
  Böttcher, J.P., Beyer, M., Meissner, F., Abdullah, Z., Sander, J., Hochst, B., Eickhoff, S., Rieckmann, J.C., Russo, C., Bauer, T., Flecken, T., Giesen, D., Engel, D., Jung, S., Busch, D.H., Protzer, U., Thimme, R., Mann, M., Kurts, C., Schultze, J.L., Kastenmüller, W. and Knolle, P.A.
  (See online at https://doi.org/10.1038/ncomms9306)
• (2015). Robust Anti-viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions. Cell 162, 1322-37
  Eickhoff, S., Brewitz, A., Gerner, M.Y., Klauschen, F., Komander, K., Hemmi, H., Garbi, N., Kaisho, T., Germain, R.N. and Kastenmuller, W.
  (See online at https://doi.org/10.1016/j.cell.2015.08.004)
• (2015). Sequence-speci c activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat Immunol. 16, 1025–33
  Herzner, A.M., Hagmann, C.A., Goldeck, M., Wolter, S., Kübler, K., Wittmann, S., Gramberg, T., Andreeva, L., Hopfner, K.P., Mertens, C., Zillinger, T., Jin, T., Xiao, T.S., Bartok, E., Coch, C., Ackermann, D., Hornung, V., Ludwig, J., Barchet, W., Hartmann, G. and Schlee, M.
  (See online at https://doi.org/10.1038/ni.3267)
• (2016) Targeted Resequencing and Functional Testing Identifies Low-Frequency Missense Variants in the Gene Encoding GARP as Significant Contributors to Atopic Dermatitis Risk. J Invest Dermatol. 136, 2380-2386
  Manz, J., Rodríguez, E., ElSharawy, A., Oesau, E.M., Petersen, B.S., Baurecht, H., Mayr, G., Weber, S., Harder, J., Reischl, E., Schwarz, A., Novak, N., Franke, A. and Weidinger, S.
  (See online at https://doi.org/10.1016/j.jid.2016.07.009)
• (2016). Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 44, 833-846
  Gaidt, M.M., Ebert, T.S., Chauhan, D., Schmidt, T., Schmid-Burgk, J.L., Rapino, F., Robertson, A.A., Cooper, M.A., Graf, T., and Hornung, V.
  (See online at https://doi.org/10.1016/j.immuni.2016.01.012)
• (2016). Inflammasome-Dependent Induction of Adaptive NK Cell Memory. Immunity 44, 1406-1421
  van den Boorn, J.G., Jakobs, C., Hagen, C., Renn, M., Luiten, R.M., Melief, C.J., Tuting, T., Garbi, N., Hartmann, G., and Hornung, V.
  (See online at https://doi.org/10.1016/j.immuni.2016.05.008)
• (2016). Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4. Proc Natl Acad Sci U S A 113, 10649-54
  Schuette, V., Embgenbroich, M., Ulas, T., Welz, M., Schulte-Schrepping, J., Draffehn, A.M., Quast, T., Koch, K., Nehring, M., König, J., Zweynert, A., Harms, F.L., Steiner, N., Limmer, A., Förster, I., Berberich-Siebelt, F., Knolle, P.A., Wohlleber, D., Kolanus, W., Beyer, M., Schultze, J.L. and Burgdorf, S.
  (See online at https://doi.org/10.1073/pnas.1605885113)
• (2016). RAGE Enhances TLR Responses through Binding and Internalization of RNA. J Immunol. 197, 4118-4126
  Bertheloot, D., Naumovski, A.L., Langhoff, P., Horvath, G.L., Jin, T., Xiao, T.S., Garbi, N., Agrawal, S., Kolbeck, R. and Latz, E.
  (See online at https://doi.org/10.4049/jimmunol.1502169)
• (2016). Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection. Nat Immunol 17, 593-603
  Beyer, M., Abdullah, Z., Chemnitz, J.M., Maisel, D., Sander, J., Lehmann, C., Thabet, Y., Shinde, P.V., Schmidleithner, L., Kohne, M., Trebicka, J., Schierwagen, R., Hofmann, A., Popov, A., Lang, K.S., Oxenius, A., Buch, T., Kurts, C., Heikenwalder, M., Fätkenheuer G., Lang, P.A., Hartmann, P., Knolle, P.A. and Schultze, J.L.
  (See online at https://doi.org/10.1038/ni.3399)
• (2017). CD8+ T Cells Orchestrate pDC-XCR1+ Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming. Immunity 46, 205-219
  Brewitz, A., Eickhoff, S., Dähling, S., Quast, T., Bedoui, S., Kroczek, R.A., Kurts, C., Garbi, N., Barchet, W., Iannacone, M., Klauschen, F., Kolanus, W., Kaisho, T., Colonna, M., Germain, R.N. and Kastenmüller, W.
  (See online at https://doi.org/10.1016/j.immuni.2017.01.003)
• (2017). Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2. Immunity 47, 1051-1066.e12
  Sander, J., Schmidt, S.V., Cirovic, B., McGovern, N., Papantonopoulou, O., Hardt, A.L., Aschenbrenner, A.C., Kreer, C., Quast, T., Xu, A.M., Schmidleithner, L.M., Theis, H., Thi Huong, L.D., Sumatoh, H.R.B., Lauterbach, M.A.R., Schulte-Schrepping, J., Günther, P., Xue, J., Baßler, K., Ulas, T., Klee, K., Katzmarski, N., Herresthal, S., Krebs, W., Martin, B., Latz, E., Händler, K., Kraut, M., Kolanus, W., Beyer, M., Falk, C.S., Wiegmann, B., Burgdorf, S., Melosh, N.A., Newell, E.W.,Ginhoux, F., Schlitzer, A. and Schultze, J.L.
  (See online at https://doi.org/10.1016/j.immuni.2017.11.024)
• (2017). Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation and protects from vascular damage in the retina. EMBO Mol Med. 2, 154-166
  Karlstetter, M., Kopatz, J., Aslanidis, A., Shahraz, A., Caramoy, A., Linnartz-Gerlach, B., Lin, Y., Lückoff, A., Fauser, S., Düker, K., Claude, J., Wang, Y., Ackermann, J., Schmidt, T., Hornung, V., Skerka, C., Langmann, T. and Neumann, H.
  (See online at https://doi.org/10.15252/emmm.201606627)
• (2017). Rescue of T-cell function during persistent pulmonary adenoviral infection by Toll-like receptor 9 activation. J Allergy Clin Immunol. 141, 416 – 419
  Holland, T., Wohlleber, D., Marx, S., Kreutzberg, T., Vento-Asturias, S., Schmitt-Mbamunyo, C., Welz, M., Janas, M., Komander, K., Eickhoff, S., Brewitz, A., Hasenberg, M., Männ, L., Gunzer, M., Wilhelm, C., Kastenmüller, W., Knolle, P., Abdullah, Z., Kurts, C. and Garbi, N.
  (See online at https://doi.org/10.1016/j.jaci.2017.06.048)
• (2017).Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity 47,789-802
  Glodde, N., Bald, T., van den Boorn-Konijnenberg, D., Nakamura, K., O'Donnell, J.S., Szczepanski, S., Brandes, M., Eickhoff, S., Das, I., Shridhar, N., Hinze, D., Rogava, M., van der Sluis, T.C., Ruotsalainen, J.J., Gaffal, E., Landsberg, J., Ludwig, K.U., Wilhelm, C., Riek- Burchardt, M., Müller, A.J., Gebhardt, C., Scolyer, R.A., Long, G.V., Janzen, V., Teng, M.W.L., Kastenmüller, W., Mazzone, M., Smyth, M.J., Tüting, T. and Hölzel, M.
  (See online at https://doi.org/10.1016/j.immuni.2017.09.012)
• (2018). RNA Aptamers recognizing murine CCL17 inhibit T cell chemotaxis and reduce contact hypersensitivity in vivo. Mol Ther. 26, 95 -104
  Fülle, L., Steiner, N., Funke, M., Gondorf, F., Pfeiffer, F., Siegl, J., Opitz, F.V., Haßel, S.K., Erazo, A.B., Schanz, O., Stunden, H.J., Blank, M., Gröber, C., Händler, K., Beyer, M., Weighardt, H., Latz, E., Schultze, J.L., Mayer, G. and Förster, I.
  (See online at https://doi.org/10.1016/j.ymthe.2017.10.005)
• (2018). The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport. Immunity 48, 911-922.e7
  Pelka, K., Bertheloot, D., Reimer, E., Phulphagar, K., Schmidt, S.V., Christ, A., Stahl, R., Watson, N., Miyake, K., Hacohen, N., Haas, A., Brinkmann, M.M., Marshak-Rothstein, A., Meissner, F. and Latz, E.
  (See online at https://doi.org/10.1016/j.immuni.2018.04.011)