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Archiv-Übersicht     Angebot Nr. 13039

Angebotsdatum: 13. September 2018
Art der Stelle: Doktorarbeit
Fachgebiet: Humanmedizin > Biologie
Titel des Themas: Maladaptation of mucosal resident memory CD4+ T cell in Inflammatory Bowel Disease

Institut: Deutsches Rheuma-Forschungszentrum
Dr. rer. nat. Susann Beetz
Chariteplatz 1
10117 Berlin
Tel.: 030 28460160   Fax.:
Bundesland: Berlin
Homepage: http://https://www.zibi-berlin.de/application/phd-projects/index.html
E-Mail Kontakt: mail

Beschreibung: The mucosal immune system drives intestinal inflammation and injury in IBD, with cytokines playing a central role in modulating inflammation. Cells of both the innate and adaptive arms of the immune response contribute to the cellular network that drives chronic intestinal inflammation through secretion of pro inflammatory cytokines.
Gut resident memory T cells are distributed throughout the organized lymphoid tissues of the gut, the lamina propria and within the intraepithelial compartment of the gut in healthy individuals. Microbiota-specific memory CD4+ T cells are enriched within gut resident memory T cells. These cells develop and generate long-lived memory T cells after barrier disruption. Using a selection of representative intestinal bacterial stimuli, we recently established that the healthy T cell repertoire, in peripheral blood and in gut tissue, contains microbiota specific T cells that had a memory phenotype and expressed high levels of TNF. Furthermore, gut resident memory T cells were even more enriched in these reactivities than in peripheral blood. Thus, a further exploration of antigen-specific memory T cells residing at barrier sites and their regulation might inform us of the potential impact of effector responses against commensals at steady state or in the context of inflammation.
The goal of this project is to decipher the dialogue between microbiota and immune system in intestinal mucosa both in health and disease to fundamentally improve our understanding of the regulation of chronic inflammatory processes.
The Volkswagen Foundation funds the project. The project will provide training in advanced mammalian cell culture, fluorescence microscopy, multicolor flow cytometry, cell sorting and access to state of the art, high-throughput sequencing techniques, and animal models of colitis as well as germ-free mouse models.
Methoden: Application Deadline: October 7th, 2018
Anfangsdatum: 1. Mai 2019
Geschätzte Dauer: 3 - 4 Jahre
Bezahlung: übliche Doktorandenstelle
Papers: Belkaid, Y., Bouladoux, N., Hand, T.W., 2013. Effector and memory T cell responses to commensal bacteria. Trends Immunol 34, 299–306.
Kaser, A., Zeissig, S., Blumberg, R.S., 2010. Inflammatory Bowel Disease. Annu Rev Immunol 28, 573–621.
Maloy, K.J., Powrie, F., 2011. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306.
Bhattacharya*, A., Hegazy*, A.N., Deigendesch, N., Kosack, L., Cupovic, J., Kandasamy, R.K., Hildebrandt, A., Merkler, D., Kühl, A.A., Vilagos, B., Schliehe, C., Panse, I., Khamina, K., Baazim, H., Arnold, I., Flatz, L., Xu, H.C., Lang, P.A., Aderem, A., Takaoka, A., Superti-Furga, G., Colinge, J., Ludewig, B., Löhning, M., Bergthaler, A., 2015. Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage. Immunity 43, 974–986.
Hegazy, A.N., Peine, M., Helmstetter, C., Panse, I., Fröhlich, A., Bergthaler, A., Flatz, L., Pinschewer, D.D., Radbruch, A., Löhning, M., 2010. Interferons Direct Th2 Cell Reprogramming to Generate a Stable GATA-3+T-bet+ Cell Subset with Combined Th2 and Th1 Cell Functions. Immunity 32, 116–128.
Hegazy*, A.N., West*, N.R., Stubbington, M.J.T., Wendt, E., Suijker, K.I.M., Datsi, A., This, S., Danne, C., Campion, S., Duncan, S.H., Owens, B.M.J., Uhlig, H.H., McMichael, A., Oxford IBD Cohort Investigators, Bergthaler, A., Teichmann, S.A., Keshav, S., Powrie, F., 2017. Circulating and Tissue-resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function is Altered During Inflammation. Gastroenterology.
Littman, D.R., Pamer, E.G., 2011. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311–323.
Macpherson, A.J., Slack, E., Geuking, M.B., McCoy, K.D., 2009. The mucosal firewalls against commensal intestinal microbes. Semin Immunopathol 31, 145–149.
Maynard, C.L., Weaver, C.T., 2009. Intestinal Effector T Cells in Health and Disease. Immunity 31, 389–400.
West*, N.R., Hegazy*, A.N., Owens, B.M.J., Bullers, S.J., Linggi, B., Buonocore, S., Coccia, M., Görtz, D., This, S., Stockenhuber, K., Pott, J., Friedrich, M., Ryzhakov, G., Baribaud, F., Brodmerkel, C., Cieluch, C., Rahman, N., Müller-Newen, G., Owens, R.J., Kühl, A.A., Maloy, K.J., Plevy, S.E., Investigators, O.I.C., Keshav, S., Travis, S.P.L., Powrie, F., 2017. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med 23, 579–589.
Sonstiges: Inflammatory Mechanisms
Supervisor: Prof. Dr. Dr. Ahmed N. Hegazy
Deutsches Rheuma-Forschungszentrum
Campus Charité Mitte
Charitéplatz 1
10117 Berlin