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Immune reactions in the intestinal mucosa: pathophysiology of intraepithelial lymphocytes

English title Immune reactions in the intestinal mucosa: pathophysiology of intraepithelial lymphocytes
Applicant Müller Christoph
Number 122560
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.10.2008 - 31.10.2011
Approved amount 600'000.00
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Keywords (7)

MUCOSAL IMMUNITY; INFLAMMATORY BOWEL DISEASES; IMMUNOREGULATION; MICROBIAL COLONISATION OF GUT LUMEN; HOMING; Inflammation; T lymphocytes

Lay Summary (English)

Lead
Lay summary
Inflammatory bowel diseases (IBD) are severe, debilitating diseases, which comprise two major clinical entities, i.e. ulcerative colitis and Crohn's disease. These chronic diseases typically start in the first two decades of life. The main symptoms are abdominal pain, diarrhea, and rectal bleeding, but general symptoms such as fever, weakness, and anemia are very common. It is generally accepted that aberrant immune reactions against intestinal antigens, including components of the intestinal commensal microflora, represent a main prerequisite for the occurrence of these disorders in genetically susceptible individuals. Hence, an improved understanding of the immunoregulatory mechanisms operative in the intestinal mucosa is relevant for elucidating the pathogenesis of IBD.The huge numbers of differentiated T cells that are present within the vast epithelial surface of the intestine contribute to the immense size of the intestinal immune system. Besides "conventional" CD4 and CD8?? T cells, "unconventional" T cells such as TCR?? T cells and CD8?? TCR?? T cells are frequently found in the intestinal epithelium. It has been estimated that there are 10 - 20 T lymphocytes per 100 epithelial cells in the human small intestine. These intraepithelial lymphocytes are believed to critically contribute to the local immunosurveillance. In our project we aim to define the functions exerted by these intestinal T cell subsets under normal conditions and during inflammatory flares. Furthermore, we are interested to define the migration properties of these "unconventional" T cells during physiological vs. inflammatory conditions.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease.
Eloranta Jyrki J, Wenger Christa, Mwinyi Jessica, Hiller Christian, Gubler Christoph, Vavricka Stephan R, Fried Michael, Kullak-Ublick Gerd A, 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.
Bifidobacterium lactis attenuates onset of inflammation in a murine model of colitis
Philippe D, Favre L, Foata F, Adolfsson O, Perruisseau-Carrier G, Vidal K, Reuteler G, Dayer-Schneider J, Mueller C, Blum S (2011), Bifidobacterium lactis attenuates onset of inflammation in a murine model of colitis, in World Journal of Gastroenterology, 17(4), 459-469.
CX3CR1 defines functionally distinct intestinal mononuclear phagocyte subsets which maintain their respective functions during homeostatic and inflammatory conditions.
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.
Epidemiology of inflammatory bowel disease: Is there a shift towards onset at a younger age?
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.
IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo
Mudter J, Yu J, Zufferey C, Brüstle A, Wirtz S, Weigmann B, Hoffman A, Schenk M, Galle PR, Lehr HA, Mueller C, Lohoff M, Neurath MF (2011), IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo, in Inflammatory Bowel Diseases, 17(6), 1343-1358.
Protein level expression of Toll-like receptors 2, 4 and 9 in renal disease.
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.
Appropriateness of therapy for fistulizing Crohn's disease: Findings from a national inflammatory bowel disease cohort
Pittet V, Juillerat P, Michetti P, Vader J-P, Burnand B, Rogler G, Beglinger C, Seibold F, Mottet C, Felley C, Gonvers J-J, Froehlich F (2010), Appropriateness of therapy for fistulizing Crohn's disease: Findings from a national inflammatory bowel disease cohort, in Alimentary Pharmacology and Therapeutics, 32(8), 1007-1016.
IL-21 induces death of marginal zone B cells during chronic inflammation.
Tortola Luigi, Yadava Koshika, Bachmann Martin F, Müller Christoph, Kisielow Jan, Kopf Manfred (2010), IL-21 induces death of marginal zone B cells during chronic inflammation., in Blood, 116(24), 5200-7.
Infliximab for Crohn's disease in the Swiss IBD Cohort Study: clinical management and appropriateness.
Juillerat Pascal, Pittet Valérie, Vader John-Paul, Burnand Bernard, Gonvers Jean-Jacques, de Saussure Philippe, Mottet Christian, Seibold Frank, Rogler Gerhard, Sagmeister Markus, Felley Christian, Michetti Pierre, Froehlich Florian, Swiss IBD Cohort Study Group (2010), Infliximab for Crohn's disease in the Swiss IBD Cohort Study: clinical management and appropriateness., in European journal of gastroenterology & hepatology, 22(11), 1352-7.
Prevalence of anaemia in inflammatory bowel disease in Switzerland: a cross-sectional study in patients from private practices and university hospitals.
Voegtlin Manuela, Vavricka Stephan R, Schoepfer Alain M, Straumann Alex, Voegtlin Juerg, Rogler Gerhard, Ballabeni Pierluigi, Pittet Valérie, Buser Andreas, Fried Michael, Beglinger Christoph, Swiss IBD Cohort Study (2010), Prevalence of anaemia in inflammatory bowel disease in Switzerland: a cross-sectional study in patients from private practices and university hospitals., in Journal of Crohn's & colitis, 4(6), 642-8.
TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis
Noti M, Corazza N, Mueller C, Berger B, Brunner T (2010), TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis, in JOURNAL OF EXPERIMENTAL MEDICINE, 207(5), 1057-1066.
Cohort profile: the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS).
Pittet Valérie, Juillerat Pascal, Mottet Christian, Felley Christian, Ballabeni Pierluigi, Burnand Bernard, Michetti Pierre, Vader John-Paul, Swiss IBD Cohort Study Group (2009), Cohort profile: the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS)., in International journal of epidemiology, 38(4), 922-31.
Eotaxin/CCL11 expression by infiltrating macrophages in rat heart transplants during ongoing acute rejection.
Zweifel Martin, Mueller Christoph, Schaffner Thomas, Dahinden Clemens, Matozan Katja, Driscoll Robert, Mohacsi Paul (2009), Eotaxin/CCL11 expression by infiltrating macrophages in rat heart transplants during ongoing acute rejection., in Experimental and molecular pathology, 87(2), 127-32.
Lack of TNFR2 expression by CD4(+) T cells exacerbates experimental colitis.
Dayer Schneider Johanna, Seibold Inge, Saxer-Sekulic Nikolina, Paredes Bruno E, Saurer Leslie, Mueller Christoph (2009), Lack of TNFR2 expression by CD4(+) T cells exacerbates experimental colitis., in European journal of immunology, 39(7), 1743-53.
Production of interferon-gamma by activated T-cell receptor-alphabeta CD8alphabeta intestinal intraepithelial lymphocytes is required and sufficient for disruption of the intestinal barrier integrity.
Zufferey Christel, Erhart Dominik, Saurer Leslie, Mueller Christoph (2009), Production of interferon-gamma by activated T-cell receptor-alphabeta CD8alphabeta intestinal intraepithelial lymphocytes is required and sufficient for disruption of the intestinal barrier integrity., in Immunology, 128(3), 351-9.
Quantitative isolation of mouse and human intestinal intraepithelial lymphocytes by elutriation centrifugation.
Binda Elisa, Erhart Dominik, Schenk Mirjam, Zufferey Christel, Renzulli Pietro, Mueller Christoph (2009), Quantitative isolation of mouse and human intestinal intraepithelial lymphocytes by elutriation centrifugation., in Journal of immunological methods, 344(1), 26-34.
Soluble TNF-alpha but not transmembrane TNF-alpha sensitizes T cells for enhanced activation-induced cell death
Muller S, Rihs S, Schneider JMD, Paredes BE, Seibold I, Brunner T, Mueller C (2009), Soluble TNF-alpha but not transmembrane TNF-alpha sensitizes T cells for enhanced activation-induced cell death, in EUROPEAN JOURNAL OF IMMUNOLOGY, 39(11), 3171-3180.
Transmembrane tumor necrosis factor alpha is required for enteropathy and is sufficient to promote parasite expulsion in gastrointestinal helminth infection.
Ierna M X, Scales H E, Mueller C, Lawrence C E (2009), Transmembrane tumor necrosis factor alpha is required for enteropathy and is sufficient to promote parasite expulsion in gastrointestinal helminth infection., in Infection and immunity, 77(9), 3879-85.

Collaboration

Group / person Country
Types of collaboration
Prof. Markus Neurath, University of Erlangen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Manfred Kopf, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Walter Reith, Univ. Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Awards

Title Year
Poster prize in Basic Immunology 2010

Associated projects

Number Title Start Funding scheme
108792 Swiss inflammatory bowel disease cohort study (SIBDCS) 01.04.2006 Cohort Studies Large
138392 Pathophysiology of intestinal intraepithelial lymphocytes: Functional heterogeneity and plasticity of CD8aa TCRab T cells 01.11.2011 Project funding (Div. I-III)
105598 Regulation of immune reactions in the intestinal mucosa: Role of intraepithelial lymphocytes 01.03.2005 Project funding (Div. I-III)

Abstract

BackgroundIntestinal intraepithelial lymphocytes (IEL) include type a T cells, i.e. the conventional MHC-restricted CD4, and CD8aß TCRaß T cells, and the type b T cells, i.e. “unconventional” T cell subsets including the CD8aa TCRaß and the TCR?d T cells. Accumulating evidence indicates an important regulatory role for CD8aa TCRaß IEL in mice and in humans, whereas TCR?d IEL appear to exert both pro-, an anti-inflammatory activities in the intestinal epithelium. Type b IEL are generally believed to be resident lymphocytes that do not recirculate once they have homed to this important T cell compartment. However, in preliminary studies we obtained evidence for an altered migration pattern of type b IEL during a potent intestinal inflammatory reaction since CD8aa TCRaß IEL may even migrate to extraintestinal sites during chronic intestinal inflammation.Working hypothesisUpon ex vivo isolation type b IEL subsets of the small and large intestine preferentially home to their sites of origin when transferred into the lymphopenic recipient mice. During a potent inflammatory reaction in the intestinal mucosa, resident type b IEL, in particular, CD8aa TCRaß, and possibly also TCR?d IEL, may change their functional capacity (e.g. enhanced secretion of IL10, and TGF-ß) and change their chemokine receptor pattern (e.g. up-regulation of CXCR3; down-regulation of CCR9) in response to a local activation in the presence of pro-inflammatory stimuli, thus, allowing the migration to sites of inflammation both at intestinal, but possibly even to extraintestinal sites. Conversely, during intestinal inflammation also circulating T cells, including Vd2 expressing TCR?d T cells, may become recruited to the intestinal epithelium at sites of intestinal inflammation.Specific Aims• Defining the tropism of mouse IEL subsets from the small, and large intestinal epithelium upon transfer into lymphopenic recipients• Defining he molecular mechanisms operative for the distinct migration patterns of IEL subsets from different intestinal locations• Defining the functional changes and alterations in the migration pattern of IEL subsets, in particularly, CD8aa TCRaß and TCR?d IEL, during inflammatory reaction in the colon• Defining the phenotypic and functional differences of human TCR?d IEL in the non-inflamed intestine and during active stages of inflammatory bowel diseases to assess whether the distinct functional activities ascribed to intestinal TCR?d IEL may be ascribed to distinct TCR?d T cell subsets.Experimental Design• Co-transfer of small intestine, and large intestine-derived IEL subsets (distinguished by a differential green-fluorescent protein (GFP) expression, and/or congenic markers, e.g. CD45.1 vs CD45.2), into lymphopenic RAG2o/o recipients to assess their homing tropism and differences in the expression profiles for chemotaxis-relevant receptors (e.g. chemokine receptors; sphingosine-1 phosphate receptor-1).• Induction of colitis by adoptive transfer of colitogenic CD4 T cells in CD8aa TCRaß containing RAG2o/o mice (i.e. gp33 specific, TCRaß tg x gp33 tg RAG2o/o mice) to follow consequences of an inflammatory stimulus on resident CD8aa TCRaß IEL (e.g. functional capacity, migration to intestinal, and extraintestinal sites, chemokine receptor expression).• Induction of CD4 T cell mediated colitis in RAG2o/o mice, reconstituted with GFP+ small intestinal IEL, and GFP- large intestinal IEL, to follow migration pattern and functional capacity of IEL from different intestinal locations during intestinal inflammation.• Analysis in vitro of the direct consequences of pro-, and anti-inflammatory stimuli on the functional, and migratory behaviour of IEL subsets, in particular, of type b IEL• Isolation of TCR?d T cell subsets from the intestinal epithelium at distinct anatomical locations in normal patients, and in patients with active inflammatory bowel diseases to assess their phenotypical, and functional capacity, with special emphasis on the differences between Vd2 vs, Vd1 TCR?d T cells (known to be preferentially present in the blood, and the intestinal epithelium of healthy individuals, respectively); presence, or absence, of CD8aa; and the differential expression of inhibitory and activating (co-) receptors, such as NKG2A, and NKG2D.Expected value of the project.The number of effector T cells residing in the intestinal IEL equals, or even exceeds, the number of splenic T cells. Hence, an improved understanding of the dynamics and the nature of functions exerted by distinct IEL subsets during potent inflammatory reactions in the intestinal mucosa is instrumental to assess their relevance for modulating also systemic immune responses. This may be particularly relevant for some of the type B IEL, known to exert regulatory activities, and, according to our preliminary results, also able to migrate to extraintestinal sites during intestinal inflammation. Hence, with the proposed studies, we expect to obtain not only information relevant for the understanding of the mechanisms operative in the maintenance of local tissue homeostasis in the intestinal mucosa, but also on how distinct regulatory T cell populations may cooperate to prevent excessive systemic inflammatory reactions, e.g. through the recruitment of regulatory type b cells out of the intestinal epithelium, during potent local inflammatory reactions in the intestinal mucosa.
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