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The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating the differentiation of CD4+, naive T-cells during chronic intestinal inflammation

English title The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating the differentiation of CD4+, naive T-cells during chronic intestinal inflammation
Applicant Scharl Michael
Number 146204
Funding scheme Project funding (special)
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.04.2013 - 31.03.2016
Approved amount 394'910.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (5)

Th17 cells; Protein Tyrosine Phosphatase non receptor type 2 (; Inflammatory Bowel Disease (IBD); T-cell differentiation; large nested project (SIBDCS)

Lay Summary (German)

Lead
Die chronisch-entzündlichen Darmerkrankungen (CED) betreffen alleine in der Schweiz etwa 15‘000 Menschen. Sie entstehen aufgrund einer fehlregulierten Immunantwort des Körpers auf verschiedenste Antigene. Ihr Auftreten wird durch Mutationen in bestimmten Risikogenen gefördert. Ein solches Risikogen ist die Protein Tyrosin Phosphatase non-receptor type 22 (PTPN22). Dieses Molekül dürfte eine wichtige Rolle in der Regulation von Entzündungszellen, insbesondere T-Lymphozyten, spielen.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Bis jetzt ist die Rolle von PTPN2 in der Entstehung der chronisch-entzündlichen Darmerkrankungen (CED) nicht geklärt. Wir gehen davon aus, dass PTPN2 eine entscheidende Rolle für die Regulation der Differenzierung und Funktion von CD4+ T-Lymphozyten spielt. In enger Zusammenarbeit mit der Schweizer IBD Kohorte wollen wir deshalb untersuchen (a) ob PTPN2 die Differenzierung bestimmter Lymphozytenarten reguliert, (b) ob PTPN2 die Funktion dieser Zellen im Rahmen eines chronischen Entzündungsgeschehen moduliert und (c) ob die krankheits-assoziierten Mutationen im PTPN2-Gen hierfür ursächlich sein könnten. Zur Beantwortung dieser Fragen werden wir zum einen in vitro Experimente mittels Zelllinien und zum anderen in vivo Experimente mittels verschiedener Mausmodelle durchführen. Um die Relevanz unserer Erkenntnisse auf die klinische Praxis übertragen zu können, sollen Gewebeproben sowie Zellen von Patienten der Schweizer IBD-Kohorte hinsichtlich der genannten Fragestellungen untersucht werden.  

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Untersuchungen dienen dazu, die Rolle von PTPN2 im Rahmen chronisch-entzündlicher Erkrankungen näher zu definieren. Hierdurch sollen wichtige Erkenntnisse über die Regulationsmechanismen von T-Zellen im Rahmen dieser Erkrankungen gewonnen werden. Die Ergebnisse dürften wichtige Erkenntnisse für die Identifizierung neuer therapeutischer Ansatzpunkte in der Behandlung chronisch-entzündlicher Erkrankungen liefern. Dies könnte letztlich entscheidend zur Verbesserung der Behandlungsmöglichkeiten nicht nur von CED-Patienten, sondern auch von Patienten mit anderen chronisch-entzündlichen Erkrankungen, wie rheumatoider Arthritis, Psoriasis oder Typ-I-Diabetes beitragen.    

Direct link to Lay Summary Last update: 28.03.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Deficiency of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Intestinal Epithelial Cells Has No Appreciable Impact on Dextran Sulphate Sodium Colitis Severity But Promotes Wound Healing.
Kasper Stephanie H, Spalinger Marianne R, Leonardi Irina, Gerstgrasser Alexandra, Raselli Tina, Gottier Claudia, Atrott Kirstin, Frey-Wagner Isabelle, Fischbeck-Terhalle Anne, Rogler Gerhard, Scharl Michael (2016), Deficiency of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Intestinal Epithelial Cells Has No Appreciable Impact on Dextran Sulphate Sodium Colitis Severity But Promotes Wound Healing., in Digestion, 93(4), 249-259.
NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22.
Spalinger Marianne R, Kasper Stephanie, Gottier Claudia, Lang Silvia, Atrott Kirstin, Vavricka Stephan R, Scharl Sylvie, Gutte Petrus M, Grütter Markus G, Beer Hans-Dietmar, Contassot Emmanuel, Chan Andrew C, Dai Xuezhi, Rawlings David J, Mair Florian, Becher Burkhard, Falk Werner, Fried Michael, Rogler Gerhard, Scharl Michael (2016), NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22., in The Journal of clinical investigation, 126(5), 1783-800.
Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease.
Spalinger Marianne R, McCole Declan F, Rogler Gerhard, Scharl Michael (2016), Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease., in World journal of gastroenterology, 22(3), 1034-44.
The Clinical Relevance of the IBD-Associated Variation within the Risk Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 2 in Patients of the Swiss IBD Cohort.
Spalinger Marianne R, Voegelin Marius, Biedermann Luc, Zeitz Jonas, Rossel Jean-Benoit, Sulz Michael Christian, Frei Pascal, Scharl Sylvie, Vavricka Stephan R, Fried Michael, Rogler Gerhard, Scharl Michael, Scharl Michael (2016), The Clinical Relevance of the IBD-Associated Variation within the Risk Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 2 in Patients of the Swiss IBD Cohort., in Digestion, 93(3), 182-92.
A cell type-specific role of protein tyrosine phosphatase non-receptor type 2 in regulating ER stress signalling.
Kasper Stephanie H, Spalinger Marianne R, Raselli Tina, Scharl Michael (2015), A cell type-specific role of protein tyrosine phosphatase non-receptor type 2 in regulating ER stress signalling., in Digestion, 91(3), 248-56.
PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis.
Spalinger M R, Kasper S, Chassard C, Raselli T, Frey-Wagner I, Gottier C, Lang S, Atrott K, Vavricka S R, Mair F, Becher B, Lacroix C, Fried M, Rogler G, Scharl M (2015), PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis., in Mucosal immunology, 8(4), 918-29.
Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation.
Spalinger Marianne R, McCole Declan F, Rogler Gerhard, Scharl Michael (2015), Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation., in Inflammatory bowel diseases, 21(3), 645-55.

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Prof. Dr. Steffen Gay Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Dr. Gerhard Rogler Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Swiss IBD Cohort Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. Stephan Vavricka Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Declan McCole United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Burkhard Becher Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Achim Weber Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
134274 Schweizer IBD Kohorten Studie 01.04.2011 Cohort Studies Large
157763 MobiPET: A mobile, small animal PET scanner for molecular imaging 01.03.2015 R'EQUIP
154488 The Microbe-Host Interface: Molecular Mechanisms Mediating Protective and Pathological Innate and Adaptive Immune Responses within the Gut 01.11.2014 Sinergia
166381 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating inflammasome activation: implications for chronic intestinal inflammation 01.04.2016 Project funding (special)

Abstract

Inflammatory bowel disease (IBD) which impacts the life of 12’000 to 15’000 people alone in Switzerland is characterized by a chronic intestinal inflammation. To further evaluate the pathogenesis and epidemiology of IBD, the Swiss IBD Cohort (SIBDC) has been founded. On a molecular level, genetic, immunological and bacterial factors contribute to IBD pathogenesis by causing a dysregulated activation of the immune system. It is well accepted that a dysbalance of T-cell subsets, in particular an elevated number of IL-17 secreting cells, plays a key role for the onset and perpetuation of IBD. Recent studies supported by the SIBDC implicated an essential role for the IBD susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in immune cell function and regulation of immune responses to bacterial antigens. The functional role of PTPN2, also a risk factor for diabetes and rheumatoid arthritis, in the pathogenesis of IBD is unknown. Using patient samples and pre-existing infrastructure from the SIBDC we will study whether PTPN2 is involved in the differentiation of CD4+ naive T-cells innate lymphoid cells (iLCs).Our hypotheses supported by recent data and studied with support of the SIBDC are that1) PTPN2 regulates differentiation of CD4+ naive T-cells as well as innate lymphoid cells (iLCs)2) PTPN2 affects function of CD4+ T-cells and iLCs during chronic inflammatory processes.3) Presence of the IBD-associated PTPN2 variants affects differentiation and function of human CD4+ T-cells and iLCs.We will study 1) whether dysfunction of PTPN2 affects differentiation of human and mouse iLCs and/or human and mouse CD4+ naive T-cells under lineage-priming conditions using molecular approaches, FACS and visual imaging. Patient samples will be obtained from the SIBDC. The support of the SIBDC will be crucial, since a large number of patients samples will be required. 2) To demonstrate the relevance for PTPN2 for function of CD4+ T-cells and iLCs we will assess expression, activity and secretion of T-cell lineage specific molecules in T-cell or immune cell specific PTPN2-/- mice. We will induce acute and chronic colitis in mice featuring an inducible T-cell- (CD4/CRE) or immune cell-specific (LYS/CRE) PTPN2 knock-out by treatment with DSS, applying a T-cell dependent transfer colitis model or by back-crossing our mice into an IL-10-deficient background in close collaboration with SIBDC members. 3) We will study whether presence of the IBD-associated PTPN2 variants affects differentiation and function of human CD4+ naive T-cells and/or iLCs isolated from non-IBD control and SIBDC patients. This aim can only be addressed in close collaboration with SIBDC due to a large number of required patient samples. Statistical data analysis will be conducted by the SIBDC statistic unit. Human primary CD4+ naive T-cells and iLC from SIBDC members and patients without IBD will be collected and genotyped for presence of the disease-associated PTPN2 variants to study the importance of PTPN2 for regulating T-cell and iLC differentiation and function in human disease. According to our hypotheses, loss of PTPN2 promotes differentiation of pro-inflammatory T-cell and iLC subsets resulting in increased production of inflammatory mediators and aggravated inflammation. Our findings obtained in close collaboration with the SIBDC will define the role for PTPN2 in the pathogenesis of chronic intestinal inflammation. They might help to identify potentially new targets for the treatment not only of IBD but also of other diseases featuring a chronic inflammation.
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