Cellular Immunology

Suppression and self-control:
How T cells fight autoimmunity

Scheffold

Introduction

Immune-mediated diseases such as Rheumatoid Arthritis, Diabetes or Multiple Sclerosis, but also inflammatory bowel diseases or allergies are thought to be initiated and maintained by T and B lymphocytes, which react against own body components (self-antigens) or harmless foreign substances (allergens, commensal microbiota). Current therapeutic approaches focus on general immune suppression instead of targeting those few disease-relevant lymphocytes. In contrast to murine models, major roadblocks towards specific therapies in humans are technical difficulties A) to identify and characterize the antigen-specific T cells and their target antigens in patients and B) to specifically approach them therapeutically.

Our group has established sensitive technologies to study antigen-specific T cells involved in immunopathology directly from patients. We characterize T cells contributing to “pathologic” or “healthy” immune reactions against autoantigens or  harmless foreign substances and describe the alterations in immunopathology. Understanding antigen-specific T cells as the drivers of disease and how these T cells can control or prevent autoimmunity or allergy has both diagnostic and  therapeutic relevance. For development of therapeutic approaches, we are trying to utilize the physiological population of regulatory T cells (Treg), known to prevent autoimmunity. We are trying to identify their physiologic target antigens and to  pecifically modify their suppressive potential in vitro, i.e. by genetic engineering.

Besides professional immune-suppressive Treg, we are also interested which mechanisms of selfcontrol inflammatory T cells employ to limit overt inflammation. Amplifying these autoregulatory circuits would be a valuable therapeutic strategy, building on re-establishment of the body’s physiological control mechanisms. Here we are focusing on the regulation of the anti-inflammatory or tissue-protective cytokines IL-10 and IL-22. Using gene expression profiling and  functional in vitro and in vivo assays, we are studying the inducing signals and the transcriptional network regulating their expression. We have identified Notch as a switch to activate IL-10 as well as IL-22 in inflammatory T cells and defined additional  critical transcription factors. We are also trying to define the physiological niche for T cell modulation by Notch and additional environmental signals, which shall be translated into in vitro T cell modulation strategies.

Selected Publications

Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M,  Worm M, Scheffold A. Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans. Cell. 2016 167(4):1067-1078.

Bacher P, Steinbach A, Kniemeyer O, Hamprecht A, Assenmacher M, Vehreschild MJGT, Vehreschild JJ, Brakhage AA, Cornely OA, Scheffold A. Fungus-specific CD4+ T cells for rapid identification of invasive pulmonary mold infection. Am J Respir Crit Care Med. 2015 191(3):348-52.

Bacher P, Kniemeyer O, Teutschbein J, Thön M, Vödisch M, Wartenberg D, Scharf DH, Koester-Eiserfunke N, Schütte M, Dübel S, Assenmacher M, Brakhage AA*, and Scheffold A*. Identification of immunogenic antigens from Aspergillus fumigatus by direct multi-parameter characterization of specific conventional and regulatory CD4+ T cells J Immunol. 2014 193(7):3332-43.

Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J, Janke M, Mockel-Tenbrinck N, Kühl A, Heimesaat M, Esser C, Im SH, Radbruch A, Rutz S and Scheffold A. Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med. 2014 211(9):1807-19.

Bacher P, Kniemeyer O, Schönbrunn A, Sawitzki B, Assenmacher M, Rietschel E, Steinbach A, Cornely OA, Brakhage AA, Thiel A, Scheffold A. Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against mucosal fungi. Mucosal Immunol. 2014 7(4):916-28

Members

Group leader
Prof. Dr. Alexander Scheffold

Scientists
Dr. rer. nat. Petra Bacher
Dr. rer. nat. Marko Janke
Dr. rer. nat. Christian Neumann

Ph.D. students
Jonas Ahlers M.Sc.
Dipl. human. biol. Stefanie Gamradt
Anna Nowak M.Sc.

Bachelor/Diploma/Master students
Lukas Heiberger B.Sc.

Technical Assistance
Thordis Hohnstein

Further members
Dr. rer. nat. Tim Meyer (guest scientist)
Dr. rer. nat. Andrej Mantei (guest scientist)

Cooperation partners

Germany
Prof. Hinrich Abken, Prof. Oliver Cornely, Angela Steinbach, Klinik I für Innere Medizin, Uniklinik Köln

Dr. Mario Assenmacher, Dr. Michael Apel, Miltenyi Biotec GmbH, Bergisch

Prof. Axel Brakhage, Dr. Olaf Kniemeyer, Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie (HKI), Jena

Dr. Uta Düesberg, Mukoviszidose Institut gGmbH, Bonn

Prof. Hermann Einsele, Dr. Michael Hudecek, Medizinische Klinik und Poliklinik II, Zentrum Innere Medizin, Uniklinik Würzburg

Prof. Charlotte Esser, Leibniz-Institut für umwelt-medizinische Forschung, Düsseldorf

Germany, Berlin
Prof. Nina Babel, Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum/Charité – Universitätsmedizin Berlin

Prof. Susanne Hartmann, FU Berlin, Fachbereich Veterinärmedizin, Institut für Immunologie

Prof. Dr. Dr. h.c. Stefan H. E. Kaufmann, Max-Planck-Institut für Infektionsbiologie

Prof. Wolfgang Uckert, Max-Delbrück-Centrum für Molekulare Medizin, Berlin

Germany, Berlin, Charité – Universitätsmedizin Berlin
Prof. Stephan Bereswil, Dr. Markus Heimesaat, Institut für Mikrobiologie und Hygiene

Dr. Eugen Feist, PD Dr. Thomas Häupl, Med. Klinik m. S. Rheumatologie und Klinische Immunologie

Dr. Anja Kühl, Med. Klinik für Gastroenterologie, Infektiologie und Rheumatologie CBF

Dr. Berit Rosche, Klinik und Hochschulambulanz für Neurologie

Dr. Carsten Schwarz, Klinik für Pädiatrie m.S. Pneumologie und Immunologie

Prof. Britta Siegmund, Dr. Jochen Maul, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie CBF

Prof. Margitta Worm, Dr. Guido Heine, Kl.für Dermatologie, Venerologie und Allergologie

Others
Dr. Sascha Rutz, Genentech, San Francisco, USA

Prof. Dr. rer. nat. Alexander Scheffold

Rheuma-Forschungslabor (RFL)
Department of Rheumatolgoy and Clinical Immunology
Charité - Universitätsmedizin Berlin
Charitéplatz 1
10117 Berlin
Gemany

Tel. +49-30-450-513-450 (Büro)
Tel. +49 30-450-513-452 (Sekretariat)
Fax +49 30-450-7-513-450
alexander.scheffold@charite.de
Charité Homepage

Keywords
Regulatory T cells
Antigen-specific T cells
Autoimmunity
Allergy
Notch

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