intestinal immunity; intraepithelial lymphocytes; intestinal microbiota; autoreactivity; colitis
Zysset Daniel Weber Benjamin Rihs Silvia Brasseit Jennifer Freigang Stefan Riether Carsten Ban (2016), TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis, in Nature Communications
, 7, 13151.
Dolowschiak Tamas, Mueller AA, Pisan LJ, Feigelman R, Felmy Boas, Sellin ME, Namineni S, Nguyen BD, Wotzka SY, Heikenwalder M, von Mering Christian, Mueller Christoph, Hardt Wolf-Dieter (2016), IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection, in Cell Host Microbe
, 20(2), 238-249.
Brasseit J, Althaus-Steiner E, Faderl M, Dickgreber N, Saurer L, Genitsch V, Dolowschiak T, Li H, Finke D, Hardt W-D, McCoy K D, Macpherson A J, Corazza N, Noti M, Mueller C (2016), CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis., in Mucosal immunology
, 9(3), 689-701.
Mueller Rebekka, Ziade Farah, Pittet Valérie, Fournier Nicolas, Ezri Jessica, Schoepfer Alain, Schibli Susanne, Spalinger Johannes, Braegger Christian, Nydegger Andreas, Swiss IBD Cohort Study (2016), Quality of Life in Swiss Paediatric Inflammatory Bowel Disease Patients: Do Patients and Their Parents Experience Disease in the Same Way?, in Journal of Crohn's & colitis
, 10(3), 269-76.
Mikocka-Walus Antonina, Pittet Valerie, Rossel Jean-Benoît, von Känel Roland, Swiss IBD Cohort Study Group (2016), Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease., in Clinical gastroenterology and hepatology : the official clinical practice journal of the American Ga
, 14(6), 829-835.
Safroneeva E, Vavricka S R, Fournier N, Pittet V, Peyrin-Biroulet L, Straumann A, Rogler G, Schoepfer A M, Swiss IBD Cohort Study Group (2015), Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease., in Alimentary pharmacology & therapeutics
, 42(8), 977-89.
Faderl Martin, Noti Mario, Corazza Nadia, Mueller Christoph (2015), Keeping bugs in check: The mucus layer as a critical component in maintaining intestinal homeostasis., in IUBMB life
, 67(4), 275-85.
Safroneeva E, Vavricka S, Fournier N, Seibold F, Mottet C, Nydegger A, Ezri J, Straumann A, Rogler G, Schoepfer A M, Swiss IBD Cohort Study Group (2015), Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients., in Alimentary pharmacology & therapeutics
, 42(5), 540-8.
Hiroz Philippe, Vavricka Stephan R, Fournier Nicolas, Safroneeva Ekaterina, Pittet Valérie, Rogler Gerhard, Schoepfer Alain M, Swiss Inflammatory Bowel Diseases Cohort Study Group (2014), Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort., in Scandinavian journal of gastroenterology
, 49(10), 1207-18.
Maillard MH, Bortolotti M, Vader JP, Mottet C, Schoepfer A, Goners JJ, Burnand B, Froehlich F, Michetti P, Pittet V, Swiss IBD Cohort Study Group (2014), Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis., in J Crohns Colitis
, 8(8), 825-834.
Thelemann Christoph, Eren Remzi Onur, Coutaz Manuel, Brasseit Jennifer, Bouzourene Hanifa, Rosa Muriel, Duval Anais, Lavanchy Christine, Mack Vanessa, Mueller Christoph, Reith Walter, Acha-Orbea Hans (2014), Interferon-γ induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis., in PloS one
, 9(1), 86844-86844.
Violi N Vietti, Vietti Violi Naïk, Schoepfer Alain M, Fournier Nicolas, Guiu Boris, Bize Pierre, Denys Alban, Swiss Inflammatory Bowel Disease Cohort Study Group (2014), Prevalence and clinical importance of mesenteric venous thrombosis in the Swiss Inflammatory Bowel Disease Cohort., in AJR. American journal of roentgenology
, 203(1), 62-9.
Vietti Violi Naïk, Schoepfer Alain M, Fournier Nicolas, Guiu Boris, Bize Pierre, Denys Alban, Swiss Inflammatory Bowel Disease Cohort Study Group (2014), Prevalence and clinical importance of mesenteric venous thrombosis in the Swiss Inflammatory Bowel Disease Cohort., in AJR. American journal of roentgenology
, 203(1), 62-9.
Schaffer Thomas, Schoepfer AM, Seibold Frank, Swiss IBD Cohort Study Group (2014), Serum ficolin-2 correlates worse than fecal calprotectin and CRP with endoscopic Crohn's disease activity., in J Crohns Colitis
, 8(9), 1125-1132.
Bjerrum Jacob T, Nielsen Ole H, Riis Lene B, Pittet Valerie, Mueller Christoph, Rogler Gerhard, Olsen Jørgen (2014), Transcriptional analysis of left-sided colitis, pancolitis, and ulcerative colitis-associated dysplasia., in Inflammatory bowel diseases
, 20(12), 2340-52.
Weber Benjamin, Schuster Steffen, Zysset Daniel, Rihs Silvia, Dickgreber Nina, Schürch Christian, Riether Carsten, Siegrist Mark, Schneider Christoph, Pawelski Helga, Gurzeler Ursina, Ziltener Pascal, Genitsch Vera, Tacchini-Cottier Fabienne, Ochsenbein Adrian, Hofstetter Willy, Kopf Manfred, Kaufmann Thomas, Oxenius Annette, Reith Walter, Saurer Leslie, Mueller Christoph (2014), TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance., in PLoS pathogens
, 10(1), 1003900-1003900.
Schoepfer Alain M, Dehlavi Mohamed-Ali, Fournier Nicolas, Safroneeva Ekaterina, Straumann Alex, Pittet Valérie, Peyrin-Biroulet Laurent, Michetti Pierre, Rogler Gerhard, Vavricka Stephan R, IBD Cohort Study Group (2013), Diagnostic delay in Crohn's disease is associated with a complicated disease course and increased operation rate., in The American journal of gastroenterology
, 108(11), 1744-1753.
Schlapbach Luregn J, Graf Rolf, Woerner Andreas, Fontana Matteo, Zimmermann-Baer Urs, Glauser David, Giannoni Eric, Roger Thierry, Müller Christoph, Nelle Mathias, Stocker Martin (2013), Pancreatic stone protein as a novel marker for neonatal sepsis., in Intensive care medicine
, 39(4), 754-63.
Pittet Valerie, Rogler Gerhard, Michetti Pierre, Fournier Nicolas, Vader John-Paul, Schoepfer Alain, Mottet Christian, Burnand Bernard, Froehlich Florian, Swiss Inflammatory Bowel Disease Cohort Study Group (2013), Penetrating or stricturing diseases are the major determinants of time to first and repeat resection surgery in Crohn's disease., in Digestion
, 87(3), 212-21.
Sulz Michael C, Siebert Uwe, Arvandi Marjan, Gothe Raffaella M, Wurm Johannes, von Känel Roland, Vavricka Stephan R, Meyenberger Christa, Sagmeister Markus, Swiss IBD Cohort Study Group (2013), Predictors for hospitalization and outpatient visits in patients with inflammatory bowel disease: results from the Swiss Inflammatory Bowel Disease Cohort Study., in European journal of gastroenterology & hepatology
, 25(7), 790-7.
Siebert Uwe, Wurm Johannes, Gothe Raffaella Matteucci, Arvandi Marjan, Vavricka Stephan R., Von Känel Roland, Begré Stefan, Sulz Michael Christian, Meyenberger Christa M., Sagmeister Markus, Swiss IBD Cohort Study Group (2013), Predictors of temporary and permanent work disability in patients with inflammatory bowel disease: results of the swiss inflammatory bowel disease cohort study., in Inflammatory bowel diseases
, 19(4), 847-855.
Scharl Michael, Mwinyi Jessica, Fischbeck Anne, Leucht Katharina, Eloranta Jyrki J, Arikkat Joba, Pesch Theresa, Kellermeier Silvia, Mair Alma, Kullak-Ublick Gerd A, Truninger Kaspar, Noreen Faiza, Regula Jaroslaw, Gaj Pawel, Pittet Valerie, Mueller Christoph, Hofmann Claudia, Fried Michael, McCole Declan F, Rogler Gerhard (2012), Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy., in Inflammatory bowel diseases
, 18(5), 900-12.
Mueller Christoph (2012), Danger-associated molecular patterns and inflammatory bowel disease: is there a connection?, in Digestive diseases (Basel, Switzerland)
, 30 Suppl 3, 40-6.
Saurer Leslie, Rihs Silvia, Birrer Michèle, Saxer-Seculic Nikolina, Radsak Markus, Mueller Christoph, Swiss IBD Cohort Study (2012), Elevated levels of serum-soluble triggering receptor expressed on myeloid cells-1 in patients with IBD do not correlate with intestinal TREM-1 mRNA expression and endoscopic disease activity., in Journal of Crohn's & colitis
, 6(9), 913-23.
Müller Christoph, Holländer Georg, Imhof Beat, Höfler Gerhard (2012), Entzündung, in Werner Böcker Helmut Denk Philipp Ulrich Heitz Holger Moch Gerald Höfler Hans Kreipe (ed.), 43-73.
Müller Christoph, Holländer Georg, Imhof Beat, Höfler Gerhard (2012), Pathologische Immunreaktionen, in Werner Böcker Helmut Denk Philipp Ulrich Heitz Holger Moch Gerald Höfler Hans Kreipe (ed.), 75-111.
Eloranta Jyrki J, Wenger Christa, Mwinyi Jessica, Hiller Christian, Gubler Christoph, Vavricka Stephan R, Fried Michael, Kullak-Ublick Gerd A (2011), Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease., in Pharmacogenetics and genomics
, 21(9), 559-64.
Philippe David, Favre Laurent, Foata Francis, Adolfsson Oskar, Perruisseau-Carrier Genevieve, Vidal Karine, Reuteler Gloria, Dayer-Schneider Johanna, Mueller Christoph, Blum Stéphanie (2011), Bifidobacterium lactis attenuates onset of inflammation in a murine model of colitis., in World journal of gastroenterology
, 17(4), 459-69.
Weber Benjamin, Saurer Leslie, Schenk Mirjam, Dickgreber Nina, Mueller Christoph (2011), CX3CR1 defines functionally distinct intestinal mononuclear phagocyte subsets which maintain their respective functions during homeostatic and inflammatory conditions., in European journal of immunology
, 41(3), 773-9.
Braegger Christian P, Ballabeni Pierluigi, Rogler Daniela, Vavricka Stephan R, Friedt Michael, Pittet Valérie (2011), Epidemiology of inflammatory bowel disease: Is there a shift towards onset at a younger age?, in Journal of pediatric gastroenterology and nutrition
, 53(2), 141-4.
Schaer Corinne, Hiltbrunner Stefanie, Ernst Bettina, Mueller Christoph, Kurrer Michael, Kopf Manfred, Harris Nicola L (2011), HVEM signalling promotes colitis., in PloS one
, 6(4), 18495-18495.
Mudter Jonas, Yu Jingling, Zufferey Christel, Brüstle Anne, Wirtz Stefan, Weigmann Benno, Hoffman Arthur, Schenk Mirjam, Galle Peter R, Lehr Hans A, Mueller Christoph, Lohoff Michael, Neurath Markus F (2011), IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo., in Inflammatory bowel diseases
, 17(6), 1343-58.
Batsford Stephen, Duermueller Ursula, Seemayer Christian, Mueller Christoph, Hopfer Helmut, Mihatsch Michael (2011), Protein level expression of Toll-like receptors 2, 4 and 9 in renal disease., in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant
, 26(4), 1413-6.
Summary BackgroundIntestinal CD8aa TCRaß T cells represent a major cell subset in the small and large intestine of mice. Despite their abundance in the intestinal epithelium, our knowledge on their antigen specificity, and the functions exerted in vivo are still limited. This may in part be ascribed to the poor survival of ex vivo isolated CD8aa TCRaß T cells in vitro. In their development they are distinct from conventional, MHC class I and class II restricted CD8aß, and CD4 TCRaß T cells. Intriguingly, CD8aa TCRaß T cells with an autoreactive TCRaß are not centrally eliminated during their intrathymic differentiation and persist in the intestinal epithelium. In contrast to the intestinal CD8aß TCRaß intraepithelial lymphocytes (IEL) CD8aa TCRaß IEL do not recirculate under homeostatic conditions and are bona fide resident T cells in the intestinal epithelium as evidenced by parabiosis experiments. Our preliminary data demonstrate an accumulation of CD8aa TCRaß T cells during a potent inflammation in the intestinal mucosa not only in the affected colonic mucosa, but also at extraintestinal sites (e.g. mesenteric and inguinal lymph nodes, spleen, blood). This dramatically altered biological behavior of the CD8aa TCRaß IEL is associated with a strong proliferation and a marked change in the cell surface expression pattern of chemotactic receptors.Working hypothesisCD8aa TCRaß T cells are functionally a heterogeneous population of T cells. Factors that influence their functional activities are the presence of self-antigens for autoreactive CD8aa TCRaß T cells; the presence of a (mostly) commensal microbiota (and their products); and potent inflammatory stimuli in the intestinal mucosa.Specific aims•Establishment of an optimized in vitro culture system for intestinal CD8aa TCRaß T cells.•Comparative analysis of the functional properties and activities of autoreactive, vs. non-autoreactive CD8aa TCRaß IEL.•Defining the impact of colonization of the gut lumen with a defined microbial flora (altered Schaedler flora, ASF) on the functional differentiation of intestinal CD8aa TCRaß IEL; assess TCRaß dependent, vs. TCRaß independent events.•Assessment of the functional and biological changes induced during intestinal inflammation in CD8aa TCRaß IEL, including the relative contribution of distinct chemotactic pathways to their altered migration during intestinal inflammation and an analysis of the molecular pathways that regulate functional, migratory and proliferative capacities in CD8aa TCRaß T cells.Experimental design•To determine the functional properties of bona-fide autoreactive vs. non-autoreactive CD8aa TCRaß IEL, the LCMV-gp33 transgenic mouse (H8 mouse), and the gp33 specific TCRaß transgenic mouse (318) on a RAG-/- background will be used for analysis. Monoclonal, autoreactive CD8aa TCRaß IEL will be obtained from double transgenic 318xH8 RAG-/- mice. The 318 RAG-/- mouse line, which lacks expression of the cognate antigen, will be used as donors of non-autoreactive CD8aa TCRaß IEL (upon FACS sorting), and intestinal CD8aa TCRaß IEL, will be isolated from H8 mice as a polyclonal population of autoreactive T cells based on gp33-tetramer staining. Methods for analysis of the different CD8aa TCRaß T cell populations include: global gene expression profiling (Affymetrix Mouse Exon 1.0 ST Arrays), FACS stainings for activation, differentiation and proliferation markers (panel of primary reagents will be adjusted also based on the results of mRNA profiling), qRT-PCR for selected cell subsets (e.g. from distinct anatomical locations), and in vitro cultures (e.g. restimulation for cytokine secretion, functional assays).•Germ-free mice (B6, Bim deficient mice) will be colonized with an altered Schaedler flora to determine the early functional and biological changes induced in the CD8aa TCRaß IEL through intestinal colonization of the gut lumen; CD8aa TCRaß IEL will be analyzed between 0 and 20 days post colonization. •To define the functional changes CD8aa TCRaß IEL by an intestinal inflammation, both, the chronic dextran sodium sulfate (DSS) model of colitis induction, and the CD4 T cell transfer model of colitis in the CD8aa TCRaß containing 318xH8 RAG-/- mice will be used; the relevance of the different chemotactic pathways for the migration of IEL subsets will be assessed in these colitis models using specific receptor deficient mice (e.g. CXCR3-/-; BLT1/Ltb4R-/-), or administration of an S1PR1 agonist.Expected value of the projectThe use of well defined experimental systems, particularly including gnotobiotic animals with a well defined microbiota, to address the specific aims in combination with in vitro cultures of (fractionated) CD8aa TCRaß cell subsets should allow to obtain relevant information on the potential plasticity and/or functional heterogeneity of this still enigmatic T cell subset, and reveal their potential involvement in regulating inflammatory reaction in the intestinal mucosa, but possibly also at extraintestinal sites. The functional characterization of CD8aa TCRaß IEL will be critical to assess their impact also on the functions of the neighboring IEC, a central issue, which so far has not been fully addressed.