SFB 633:  Induction and Modulation of T cell Mediated Immune Responses in the Gastrointestinal Tract

• Subject Area: Medicine
• Term: from 2003 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5485888

• Final Report Year: 2015

Final Report Abstract

The immune system of the gastrointestinal tract has a unique position since it represents the largest interface of the human body. The associated exposure to a multitude of microorganisms – mostly harmless and beneficial commensals - requires a differential reaction towards these microrganisms as well as food antigens in contrast to pathogens. Hence, the balance in between tolerance and inflammatory reactions is pivotal for the gastrointestinal tract. Thus it is not surprising that inflammatory bowel diseases, besides allergies, not only belong to the most abundant immune-mediated diseases but furthermore that the experimental interference with numerous regulatory pathways results in intestinal inflammation that translated to more than 50 animal models for intestinal inflammation. Accordingly, localization, development, and composition of immune cells in the intestine, development of lymphatic structures, reactivity and functional specialization, homing and life cycle of cells are unique. Nowhere else, but in the mucosal immune system architecture, function and systemic impact depend on the interaction with the complex microbiota. The main goal of the SFB633 was to elucidate these interactions in an interdisciplinary approach. The PI of the projects provided a profound expertise in three main areas: i) in the biology of T cells in terms of specialized effector cells playing a central role as versatile regulators for the reactivity of the mucosal immune system, ii) in the analysis and modulation of the intestinal microbiota, acknowledging them as essential reaction partners and stimulators for the physiology and pathology of the mucosal immune system, and iii) in the clinical representation of inflammatory diseases and infections of the gastrointestinal tract, but also of other organ systems corresponding to mucosal reactions. This unique combination not only allowed for introducing novel methods and concepts for the analysis of the complex system of gastrointestinal immune reactions, but was also instrumental in translating the findings into new strategies for the therapy of chronic-inflammatory diseases and for the protection from infectious diseases.

Publications

• J Exp Med. 2004. 199:303-13
  Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feurer M, Debes GF, Lauber F, Frey O, Przybylski GK, Niesner U, de la Rosa M, Schmidt CA, Bräuer R, Buer J, Scheffold A, Hamann A
  
• Design of siRNAs producing unstructured guide-RNAs results in improved RNA interference efficiency. Nat Biotechnol. 2005. 23:1440-4
  Patzel V, Rutz S, Dietrich I, Köberle C, Scheffold A, Kaufmann SH
  
• Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat Med. 2005. 11:1118-24
  Frentsch M, Arbach O, Kirchhoff D, Moewes B, Worm M, Rothe M, Scheffold A, Thiel A
  
• Early intrahepatic antigen-specific retention of naive CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice. Hepatology. 2005. 42:1063-71
  Bertolino P, Schrage A, Bowen DG, Klugewitz K, Ghani S, Eulenburg K, Holz L, Hogg N, McCaughan GW, Hamann A
  
• Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 2005. 437:141-6
  Willimsky G, Blankenstein T
  
• Identification of immunodominant CD4+ T cell epitopes in patients with Yersinia-induced reactive arthritis by cytometric cytokine secretion assay. Arthritis Rheum. 2006. 54:34583-90
  Thiel A, Wu P, Lanowska M, Dong J, Radbruch A, Sieper J
  
• Proteasome-mediated degradation of IkappaBalpha and processing of p105 in Crohn disease and ulcerative colitis. J Clin Invest. 2006. 116:3195-203
  Visekruna A, Joeris T, Seidel D, Kroesen A, Loddenkemper C, Zeitz M, Kaufmann SH, Schmidt- Ullrich R, Steinhoff U
  
• Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli. Gut. 2007. 56:941-8
  Heimesaat MM, Fischer A, Jahn HK, Niebergall J, Freudenberg M, Blaut M, Liesenfeld O, Schumann RR, Göbel UB, Bereswill S
  
• Autoregulation of Th1-mediated inflammation by twist1. J Exp Med. 2008. 205:1889-901
  Niesner U, Albrecht I, Janke M, Doebis C, Loddenkemper C, Lexberg MH, Eulenburg K, Kreher S, Koeck J, Baumgrass R, Bonhagen K, Kamradt T, Enghard P, Humrich JY, Rutz S, Schulze- Topphoff U, Aktas O, Bartfeld S, Radbruch H, Hegazy AN, Löhning M, Baumgart DC, Duchmann R, Rudwaleit M, Häupl T, Gitelman I, Krenn V, Gruen J, Sieper J, Zeitz M, Wiedenmann B, Zipp F, Hamann A, Janitz M, Scheffold A, Burmester GR, Chang HD, Radbruch A
  
• Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J Exp Med. 2008. 205:1687-1700
  Willimsky G, Czéh M, Loddenkemper C, Gellermann J, Schmidt K, Wust P, Stein H, Blankenstein T
  
• Notch regulates IL-10 production by T helper 1 cells. Proc Natl Acad Sci USA. 2008. 105:3497-502
  Rutz S, Janke M, Kassner N, Hohnstein T, Krueger M, Scheffold A
  
• Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of interleukin-17. J Exp Med. 2009. 206:3047-59
  Muñoz M, Heimesaat MM, Danker K, Struck D, Lohmann U, Plickert R, Bereswill S, Fischer A, Dunay IR, Wolk K, Loddenkemper C, Krell HW, Libert C, Lund LR, Frey O, Hölscher C, Iwukura Y, Ghilardi N, Ouyang W, Kamradt T, Sabat R, Liesenfeld O
  
• Priming of CD4(+) T cells by liver sinusoidal endothelial cells induces CD25(low) forkhead box protein 3(-) regulatory T cells suppressing autoimmune hepatitis. Hepatology. 2009. 50:1904-13
  Kruse N, Neumann K, Schrage A, Derkow K, Schott E, Erben U, Kühl A, Loddenkemper C, Zeitz M, Hamann A, Klugewitz K
  
• Impaired immune functions of monocytes and macrophages in Whipple's disease. Gastroenterology. 2010. 138:210-20
  Moos V, Schmidt C, Geelhaar A, Kunkel D, Allers K, Schinnerling K, Loddenkemper C, Fenollar F, Moter A, Raoult D, Ignatius R, Schneider T
  
• MyD88-signalling in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity. 2010. 33:777-90
  Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P, Kühl, AA, Loddenkemper C, Haury M, Nedospasov SA, Kaufmann SHE, Steinhoff U, Calado D, Fillatreau S
  
• MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versushost disease. Gut. 2010. 59:1079-87
  Heimesaat MM, Nogai A, Bereswill S, Plickert R, Fischer A, Loddenkemper C, Steinhoff U, Tchaptchet S, Thiel E, Freudenberg MA, Göbel UB, Uharek L
  
• Persistence of effector memory Th1 cells is regulated by Hopx. Eur J Immunol. 2010. 40:2993-3006
  Albrecht I, Niesner U, Janke M, Menning A, Loddenkemper C, Kühl AA, Lepenies I, Lexberg MH, Westendorf K, Hradilkova K, Grün J, Hamann A, Epstein JA, Chang HD, Tokoyoda K, Radbruch A
  
• The immune reconstitution inflammatory syndrome in Whipple disease: a cohort study. Ann Intern Med. 2010. 153:710-7
  Feurle GE, Moos V, Schinnerling K, Geelhaar A, Allers K, Biagi F, Blaker H, Moter A, Loddenkemper C, Jansen A, Schneider T
  
• The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol. 2010. 11:1057-62
  Stittrich AB, Haftmann C, Sgouroudis E, Kühl AA, Hegazy AN, Panse I, Riedel R, Flossdorf M, Dong J, Fuhrmann F, Heinz GA, Fang Z, Li N, Bissels U, Hatam F, Jahn A, Hammoud B, Matz M, Schulze FM, Baumgrass R, Bosio A, Mollenkopf HJ, Grün J, Thiel A, Chen W, Höfer T, Loddenkemper C, Löhning M, Chang HD, Rajewsky N, Radbruch A, Mashreghi MF
  
• Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. Blood. 2011. 117: 2839-46
  Steinfelder S, Floess S, Engelbert D, Haeringer B, Baron U, Rivino L, Steckel B, Gruetzkau A, Olek S, Geginat J, Huehn J, Hamann A
  
• Modulation of the CD4+ T-cell response by helicobacter pylori depends on known virulence factors and bacterial cholesterol and cholesterol α-glucoside content. J Infect Dis. 2011. 204:1339-48
  Beigier-Bompadre M, Moos V, Belogolova E, Allers K, Schneider T, Churin Y, Ignatius R, Meyer TF, Aebischer T
  
• CCR7 deficiency causes diarrhea associated with altered ion transport in colonocytes in the absence of overt colitis, Mucosal Immunol. 2012. 5:377-87
  Schumann M, Winter S, Wichner K, May C, Kühl AA, Batra A, Siegmund B, Zeitz M, Schulzke JD, Lipp M, Hopken UE
  (See online at https://doi.org/10.1038/mi.2012.15)
• Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4 + T cells via retinoic acid. Hepatology. 2012. 55:1976-84
  Neumann K, Kruse N, Szilagyi B, Erben U, Rudolph C, Flach A, Zeitz M, Hamann A, Klugewitz K
  (See online at https://doi.org/10.1002/hep.24816)
• Mesenteric fat - control site for bacterial translocation in colitis? Mucosal Immunol. 2012. 5:580-91
  Batra A, Heimesaat MM, Bereswill S, Fischer A, Glauben R, Kunkel D, Scheffold A, Erben U, Kühl A, Loddenkemper C, Lehr HA, Schumann M, Schulzke JD, Zeitz M, Siegmund B
  (See online at https://doi.org/10.1038/mi.2012.33)
• Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn's disease. Gut. 2013. 62:852-62
  Kredel LI, Batra A, Stroh T, Kühl AA, Zeitz M, Erben U, Siegmund B
  (See online at https://doi.org/10.1136/gutjnl-2011-301424)
• Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer. Blood. 2013.121:1740-48
  Schmidt K, Zilio S, Schmollinger JC, Bronte V, Blankenstein T, Willimsky G
  (See online at https://doi.org/10.1182/blood-2012-06-436568)
• Fas expression by tumor stroma is required for cancer eradication. Proc Natl Acad Sci USA. 2013. 110:2276-81
  Listopad J, Kammertoens T, Anders K, Silkenstedt B, Willimsky G, Schmidt K, Kühl A, Loddenkemper C, Blankenstein T
  (See online at https://doi.org/10.1073/pnas.1218295110)
• Non-redundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science. 2013. 342:1243-6
  Kruglov AA, Grivennikov SI, Kuprash DV, Winsauer C, Prepens S, Seleznik GM, Eberl G, Littman DR, Heikenwalder M, Tumanov AV, Nedospasov SA
  (See online at https://doi.org/10.1126/science.1243364)
• RORγt+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity. 2013. 38:1223-35
  Glatzer T, Killig M, Meisig J, Ommert I, Luetke-Eversloh M, Babic M, Paclik D, Blüthgen N, Seidl R, Seifarth C, Gröne J, Lenarz M, Stölzel K, Fugmann D, Porgador A, Hauser A, Karlas A, Romagnani C
  (See online at https://doi.org/10.1016/j.immuni.2013.05.013)
• Transition from an autoimmune-prone state to fatal autoimmune disease in CCR7 and RORγt double-deficient mice is dependent on gut microbiota. J Autoimmun. 2013. 47:58-72
  Wichner K, Fischer A, Winter S, Tetzlaff S, Heimesaat MM, Bereswill S, Rehm A, Lipp M, Höpken UE
  (See online at https://doi.org/10.1016/j.jaut.2013.08.007)
• Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance. J Clin Invest. 2013. 123:1032-43
  Willimsky G, Schmidt K, Loddenkemper C, Gellermann J, Blankenstein T
  (See online at https://doi.org/10.1172/JCI64742)
• A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. Gut. 2014. Dec 24. pii: gutjnl-2014-307949
  Schlaermann P, Toelle B, Berger H, Schmidt SC, Glanemann M, Ordemann J, Bartfeld S, Mollenkopf HJ, Meyer TF
  (See online at https://doi.org/10.1136/gutjnl-2014-307949)
• CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice. Hepatology. 2014. 59:601-11
  Seidel D, Eickmeier I, Kühl AA, Hamann A, Loddenkemper C, Schott E
  (See online at https://doi.org/10.1002/hep.26702)
• CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice. Hepatology. 2014. 59:601-11
  Seidel D, Eickmeier I, Kühl AA, Hamann A, Loddenkemper C, Schott E
  (See online at https://doi.org/10.1002/hep.26702)
• Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLoS Pathog. 2014. 10:e1004441
  Luetke-Eversloh M, Hammer Q, Durek P, Nordström K, Gasparoni G, Pink M, Hamann A, Walter J, Chang HD, Dong J, Romagnani C
  (See online at https://doi.org/10.1371/journal.ppat.1004441)
• Human RORγt+ CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity. 2014. 41:988-1000
  Montaldo E, Teixeira-Alves LG, Glatzer T, Hamann W, Babic M, Paclik D, Stölzel K, Gröne J, Lozza L, Juelke K, Matzmohr N, Loiacono F, Petronelli P, Huntington ND, Moretta L, Mingari MC, Romagnani C
  (See online at https://doi.org/10.1016/j.immuni.2014.11.010)
• Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med. 2014. 211:1807-19
  Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J, Janke M, Rudolph C, Mockel-Tenbrinck N, Kühl AA, Heimesaat MM, Esser C, Im SH, Radbruch A, Rutz S, Scheffold A
  (See online at https://doi.org/10.1084/jem.20131548)
• Inflammation-induced formation of fat associated lymphoid clusters requires TNFR signaling and natural killer T cells. Nat Immun. 2015. 16:819-28
  Bénézech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, Zhang Y, Nayar S, Jones LH, Flores-Langarica A, McIntosh A, Marshall J, Barone F, Besra G, Miles K, Allen JE, Gray M, Kollias G, Cunningham AF, Withers D, Toellner KM, Jones ND, Veldhoen M, Nedospasov SA, McKenzie AN, Caamaño JH
  (See online at https://doi.org/10.1038/ni.3215)
• Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity. 2015. 42:321-31
  Muñoz M, Eidenschenk C, Ota N, Wong K, Lohmann U, Kühl AA, Wang X, Manzanillo P, Li Y, Rutz S, Zheng Y, Diehl L, Kayagaki N, van Lookeren-Campagne M, Liesenfeld O, Heimesaat M, Ouyang W
  (See online at https://doi.org/10.1016/j.immuni.2015.01.011)
• Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice. Mucosal Immunol. 2015. May 6
  Lemke A, Kraft M, Roth K, Riedel R, Lammerding D, Hauser AE
  (See online at https://doi.org/10.1038/mi.2015.38)