Project

Back to overview

Intestinal tissue resident memory T cells in inflammation and homeostasis

English title Intestinal tissue resident memory T cells in inflammation and homeostasis
Applicant Müller Christoph
Number 170084
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.11.2016 - 31.10.2019
Approved amount 525'000.00
Show all

Keywords (5)

T cell differentiation; Intestinal Immunity; Immunoregulation; Inflammatory Bowel Diseases; Tissue resident memory T cells

Lay Summary (German)

Lead
Die Vorgänge, die in chronisch- entzündlichen Erkrankungen zur Auslösung eines erneuten Schubes der Erkrankung führen, sind weitgehend unklar. Anhand eines Mausmodells einer chronischen Darmentzündung werden wir unsere Hypothese testen, dass Gedächtnis T Zellen, die sich im Gewebe aufhalten ("Tissue-resident memory T cells") dafür verantwortlich sind und werden versuchen durch gezielte Interventionen das erneute Aufflackern der Krankheit zu verzögern oder sogar zu verhindern.
Lay summary

Chronische Entzündungskrankheiten wie Morbus Crohn oder Kolitis ulzerosa (Inflammatory Bowel Diseases, IBD) sind charakterisiert durch eine Abfolge von Krankheitsschüben und beschwerdefreien Intervallen (Remission).

Die Ursachen, die bei Patienten in Remission erneut zu einem Aufflackern der Entzündung („flare“, „relapse“) führen, sind weitgehend unbekannt. Wir haben kürzlich ein Mausmodell einer reversiblen Kolitis etabliert, um diese Prozesse zu untersuchen. Interessanterweise sehen wir in diesem CD4 T Zell-abhängigen Kolitis-Modell nach der Induktion einer Remission (mittels anti-CD4 Antikörper Behandlung) nach mehr als 20 Tagen wiederum einen Entzündungsschub. Dieser Schub ist assoziiert mit einer vorhergehenden Expansion von CD4 T Zellen, die vermehrt im Blut zirkulieren.

Mit den geplanten Versuchen werden wir die Hypothese testen, dass sogenannte „Tissue-resident memory T cells (T(RM) T cells) für das Wiederaufflackern der Entzündung verantwortlich sind. Gleichzeitig werden wir untersuchen, welche Eigenschaften für T(RM) T Zellen spezifisch sind und wie sich die Funktionen dieser T(RM) T Zellen ggf. durch Umgebungsfaktoren verändern lassen. Hier interessiert insbesondere die Frage, welche Faktoren allenfalls regulierend auf die Differenzierung dieser T(RM) T Zellen in entzündungsfördernde (pro-inflammatorische ) Effektor-T Zellen wirken und dadurch das Aufflackern der Entzündung verzögern oder sogar verhindern könnten.

 

Direct link to Lay Summary Last update: 25.10.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Oral Mucosal Immunity and Microbiome
Mueller Christoph, Kwong Chung Cheong K. C., Faderl Martin R., Brasseit Jennifer, Zysset Daniel (2019), Oral Mucosal Immunity and Microbiome, in Bostanci N, Belibasakis G, Hajishengallis G, Curtis M (ed.), Springer International Publishing, Cham, 97-105.
Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity
Liu Qingkun, Johnson Emily M., Lam Rachel K., Wang Qian, Bo Ye Hong, Wilson Edward N., Minhas Paras S., Liu Ling, Swarovski Michelle S., Tran Stephanie, Wang Jing, Mehta Swapnil S., Yang Xi, Rabinowitz Joshua D., Yang Samuel S., Shamloo Mehrdad, Mueller Christoph, James Michelle L., Andreasson Katrin I. (2019), Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity, in Nature Immunology, 20(8), 1023-1034.
Cohort Profile Update: The Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS)
Pittet Valérie, Michetti Pierre, Mueller Christoph, Braegger Christian P, von Känel Roland, Schoepfer Alain, Macpherson Andrew J, Rogler Gerhard, Anderegg Claudia, Bauerfeind Peter, Beglinger Christoph, Begré Stefan, Belli Dominique, Bengoa José M, Biedermann Luc, Bigler Beat, Binek Janek, Blattmann Mirjam, Boehm Stephan, Borovicka Jan, Braegger Christian P, Brunner Nora, Bühr Patrick, Burnand Bernard, et al. (2019), Cohort Profile Update: The Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), in International Journal of Epidemiology, 48(2), 385-386f.
Microbial network disturbances in relapsing refractory Crohn’s disease
Yilmaz Bahtiyar, Juillerat Pascal, Øyås Ove, Ramon Charlotte, Bravo Francisco Damian, Franc Yannick, Fournier Nicolas, Michetti Pierre, Mueller Christoph, Geuking Markus, Pittet Valerie E. H., Maillard Michel H., Rogler Gerhard, Wiest Reiner, Stelling Jörg, Macpherson Andrew J. (2019), Microbial network disturbances in relapsing refractory Crohn’s disease, in Nature Medicine, 25(2), 323-336.
Entzündung
MüllerChristoph, HöflerGerald, ImhofBeat A, Holländer Georg A (2019), Entzündung, in Moch Holger, Kreipe Hans, Höfler Gerald (ed.), Elsevier GmbH, München, 43-73.
Pathologische Immunreaktionen
MüllerChristoph, HöflerGerald, ImhofBeat A, HolländerGeorg A, BabaHideo A (2019), Pathologische Immunreaktionen, in Kreipe Hans, Höfler Gerald, Moch Holger (ed.), Elsevier GmbH, München D, 75-115.
Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions
Wang Junhua, Goepfert Christine, Mueller Norbert, Piersigilli Alessandra, Lin Renyong, Wen Hao, Vuitton Dominique A., Vuitton Lucine, Mueller Christoph, Gottstein Bruno (2018), Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions, in Immunology, 154(1), 76-88.
Cohort Profile: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS)
Safroneeva Ekaterina, Saner Catherine, Rossel Jean-Benoît, Golay Delphine, Pittet Valérie, Godat Sébastien, Diem Stefan, Aepli Patrick, Sawatzki Mikael, Borovicka Jan, Burgmann Konstantin, Juillerat Pascal, Netzer Peter, Sendensky Alexander, Hruz Petr, Girardin Marc, Biedermann Luc, Greuter Thomas, Vavricka Stephan, Michetti Pierre, Mueller Christoph, Straumann Alex, Schoepfer Alain M. (2018), Cohort Profile: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS), in Inflammatory Intestinal Diseases, 2(3), 163-170.
Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation
Brasseit Jennifer, Kwong Chung Cheong K. C., Noti Mario, Zysset Daniel, Hoheisel-Dickgreber Nina, Genitsch Vera, Corazza Nadia, Mueller Christoph (2018), Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation, in Frontiers in Immunology, 9, 1-12.
Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease
Lang B. M., Biedermann L., van Haaften W. T., de Vallière C., Schuurmans M., Begré S., Zeitz J., Scharl M., Turina M., Greuter T., Schreiner P., Heinrich H., Kuntzen T., Vavricka S. R., Rogler G., Beerenwinkel N., Misselwitz B. (2018), Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease, in Alimentary Pharmacology & Therapeutics, 47(1), 55-66.
TREM-1 promotes intestinal tumorigenesis
Saurer Leslie, Zysset Daniel, Rihs Silvia, Mager Lukas, Gusberti Matteo, Simillion Cedric, Lugli Alessandro, Zlobec Inti, Krebs Philippe, Mueller Christoph (2017), TREM-1 promotes intestinal tumorigenesis, in Scientific Reports, 7(1), 14870-14870.
The ESRP1-GPR137 axis contributes to intestinal pathogenesis
Mager Lukas Franz, Koelzer Viktor Hendrik, Stuber Regula, Thoo Lester, Keller Irene, Koeck Ivonne, Langenegger Maya, Simillion Cedric, Pfister Simona P, Faderl Martin, Genitsch Vera, Tcymbarevich Irina, Juillerat Pascal, Li Xiaohong, Xia Yu, Karamitopoulou Eva, Lyck Ruth, Zlobec Inti, Hapfelmeier Siegfried, Bruggmann Rémy, McCoy Kathy D, Macpherson Andrew J, Müller Christoph, Beutler Bruce, et al. (2017), The ESRP1-GPR137 axis contributes to intestinal pathogenesis, in eLife, 6, 1-27.
Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy
Hussain Maryam, Borcard Loïc, Walsh Kevin P., Pena Rodriguez Maria, Mueller Christoph, Kim Brian S., Kubo Masato, Artis David, Noti Mario (2017), Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy, in Journal of Allergy and Clinical Immunology.

Collaboration

Group / person Country
Types of collaboration
Klaas van Gisbergen, Sanquin/University of Amsterdam Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Phil Beachy, Stanford University, Stem Cell Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Swiss IBD Cohort Study (SNF # 33CS30_148422) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Uwe Sauer, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Andrew Macpherson, Universität Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Wolf-Dieter Hardt, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Sebastian Zundler, Universität Erlangen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Walter Reith, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Kati Andreasson, Dept of Neurology and Neurosciences, Stanford, CA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
1. Conference on Oral Microbiome and oral mucosa Talk given at a conference Pathobiont 26.09.2018 Kolumbari (Kreta), Greece Müller Christoph;
European Research Group in Oral Biology-Annual Meeting (invited speaker) Talk given at a conference “Inflammation amplifiers: new players and unexpected roles” 06.05.2017 Prangins, Switzerland Müller Christoph;


Awards

Title Year
Honorary member, Swiss Society of Allergology and Immunology 2016

Associated projects

Number Title Start Funding scheme
189277 Relapsing-remitting intestinal inflammation: the contribution of resident immune cells 01.11.2019 Project funding (special)
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP
148422 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2014 Cohort Studies Large
189277 Relapsing-remitting intestinal inflammation: the contribution of resident immune cells 01.11.2019 Project funding (special)
136286 Recovery of intestinal homeostasis after microbial or immunological challenge 01.12.2011 Sinergia
154414 The Host-Microbial Superorganism 01.01.2015 Sinergia
138392 Pathophysiology of intestinal intraepithelial lymphocytes: Functional heterogeneity and plasticity of CD8aa TCRab T cells 01.11.2011 Project funding (Div. I-III)
138392 Pathophysiology of intestinal intraepithelial lymphocytes: Functional heterogeneity and plasticity of CD8aa TCRab T cells 01.11.2011 Project funding (Div. I-III)

Abstract

The concept of tissue-resident memory (TRM) cells that reside in non-lymphoid tissues preferentially at the barrier tissues of the body (skin, mucosae), and which strategically complement the central memory (TCM) T cells in secondary lymphoid organs and the circulating effector memory (TEM) T cells, represents an important conceptual advance with relevance for our understanding of the mechanisms operative also in chronic remitting-relapsing inflammatory disorders such as Crohn’s disease and ulcerative colitis where the onset of a relapse is unpredictable. Here we propose to define reliable markers for identifying TRM cells; to determine how the generation, and differentiation of (intestinal) TRM cells is regulated, and to explore strategies to potentially extend the remission period using a recently established novel mouse model of remitting - relapsing colitis.Working hypothesis The generation and persistence of TRM is critically regulated by Regulator of G-protein Signaling (Rgs) - genes, which can be used as a positive identifier of TRM cells. The functional and phenotypic differentiation of locally generated CD4 TRM cells is influenced by the intestinal microenvironment. During chronic intestinal inflammation, CD4 TRM cells progressively differentiate into distinct CD4 T cell subsets, including highly pro-inflammatory CD4 TRM subsets, which cause relapsing disease. Specific interventions to block this progressive differentiation will extend the remission phase. Specific AimsBased on our current data in mouse models of colitis we propose: •To identify functional markers that allow the identification of tissue resident memory T cells (TRM) in the intestinal mucosa (but likely also in other barrier tissues).•To use our recently established mouse model of a remitting - relapsing colitis in mice to follow the functional and phenotypic characteristics of CD4 TRM in the intestinal mucosa in homeostatic and inflammatory conditions.•To determine the distinct requirements for the generation, persistence and functional differentiation of intestinal CD4 TRM cells.•To assess specific interventions aimed at either the intestinal microbiota, the local immune homeostasis and the intestinal stromal cells for their impact on the differentiation and activation of the local CD4 TRM cells in order to extend the remission phase (or even: prevent further relapses).Experimental design TRM cells at barrier tissues consist of a wide array of T cells includinge both “unconventional” (or “innate”) T cells, and and conventional MHC class I and II restricted CD8?? and CD4 TCR?? T cells. , which may differ in the spectrum of antigenic epitopes recognized, their restriction elements, and their effector functions. We propose to initially look (as “pars pro toto”) aton two resident T cell subsets that so far received limited attention; i.e. the unconventional CD8?? TCR?? T cells, which in mice are preferentially found in the small intestinal epithelium and the intestinal CD4 TRM cells. As a model of remitting - relapsing colitis the CD4 CD45RBhi T cell induced mouse model of colitis in lymphopenic recipients will be used, where active colitis is rapidly reversed by the administration of a depleting anti-CD4 mAb. Anti-CD4 treated mice, however, tend to reproducibly relapse within 20-22 days after the treatment. Using RNASeq analysis together with the appropriate bioinformatic support for analysis we expect to define core transcriptome profiles of intestinal CD8?? TCR?? and CD4 TRM cells during homeostatic, inflammatory, remitting, and relapsing conditions. These transcriptomes will be compared with those of intestinal also from TCR?? T cells and and CD8?? TCR?? T cells during homeostasis. Results obtained are expected to allow the identification of signaling pathways that regulate the generation and further differentiation of TRM cells in homeostasis and inflammation. These candidates, together with candidates we identified in our ongoing work, will the be tested using co-transfer of CD45 congenic CD4 T cell subsets from genetically modified donor mice, vs. WT CD4 T cell subsets to directly determine the impact of a gene of interest on the generation, localization, and persistence, and functional differentiation of TRM cells in the intestinal mucosa. With this insight, we will finally attempt to interfere with those TRM cells that give rise to “pathogenic” effector T cells (and TRM cells) in chronic intestinal inflammation and cause relapsing colitis. Approaches to be initially tested for their impact on remitting vs. relapsing colitis include:•Interfering with the normal microbiota of the host•Interfering with distinct signaling pathways used by the pathogenic CD4 TRM cells,•Attempts to modulate pharmacologically the intestinal stromal cell compartment using agonists (vs. antagonists) of the Hedgehog (Hh) signaling pathway to generate a local environment that favors the generation of homeostasis-supporting CD4 TRM cells and thus, extends the remission interval.Expected value of the project •Define a core transcriptome to positively identify (and distinguish) (intestinal) TRM cells and distinguish them from circulating cells), as a rationale for the subsequent generation of a reporter mouse to follow TRM cells in vivo •Define the requirements and signaling pathways involved) in the generation of (TRM cells (notably, CD4 TRM cells)•Define the (progressive ) differentiation of CD4 TRM cells in the intestinal mucosa during homeostasis, colitis, remission and relapse•Determine the factors that regulate the functional characteristics of CD4 TRM cells as key players in mediating the decision-making between inflammation vs. remission vs. relapsing inflammatory diseases.With the present work we expect to gain insight into the fundamental mechanisms that regulate the generation, persistence and functional activity of TRM cells in barrier tissues, which critically determine the outcome of inflammatory disease. We also aim to identify novel pathways that may directly affect the generation and differentiation of pro-inflammatory CD4 TRM cells, and hence, represent potential targets for treating patients with relapsing intestinal inflammatory disorders.
-