Experimental Rheumatology

Epigenetics, molecular regulation of T cell
differentiation, and novel concepts for the therapy of autoimmune/chronic inflammatory diseases

Hamann

Introduction

Our group is focusing on two areas: I) epigenetics and II) immune regulation/translation.

I) Here we study the epigenetic impact on CD4+ T cell differentiation in health and under chronic inflammatory conditions, to understand how long-term shifts in the phenotype and functional profile of T cells are maintained on the molecular level.

Our work has documented the impact of epigenetic regulation for the stable expression of the master transcription factor Foxp3 in regulatory T cells and for several homing-related molecules. More recently, as members of the DEEP consortium,  we established full epigenomes of human T cells and studied the role of epigenetics for T memory cell differentiation. This work:

• unravelled a major loss of genome-wide DNA methylation with memory development;

• supported a linear model of differentiation in circulating T cells in the order naïve -> Tcm (T central memory cells) -> Tem (T effector memory re-expressing cells) -> Temra (T effector memory re-expressing CD45RA cells),

• highlighted various known or novel transcription factors regulating the memory differentiation process and which are under epigenetic expression control.

We expect that this research will help to better understand the features of T cells fuelling chronic inflammation. Moreover, it might lead to the identification of novel targets and tools for the therapeutic modulation of T cells in inflammatory diseases.

II) Here we tested several approaches to strengthen self-tolerance: a) by vaccination with chemically modified peptides and, b) by vaccination with peptides coupled to a transporter module targeting it into the (tolerogenic) compartment of  mucosal tissues. In addition, we searched by high throughput screening for novel compounds able to induce inhibitory cytokines of the immune system such as IL-27, IL-35, IL-10, or to induce Foxp3.

Ad a) We found that coupling of peptides to synthetic carriers (PEG) or nanobeads is enhancing their tolerogenic effect and is able to inhibit the development of experimental autoimmune encephalomyelitis, a murine model for Multiple Sclerosis; yet application at the peak of disease was so far not effective.

Ad b) Use of a transporter peptide improved the tolerogenic effect of local vaccination, but in total, the mucosal pathway was not as tolerogenic as predicted.

Our screenings for compounds targeting inhibitory pathways delivered a number of candidates that increase EBI3 (a component of the inhibitory cytokines IL-27 and IL-35) and simultaneously down-regulated effector cytokines. In addition, one substance was found that induces Foxp3 in mouse T cells. In cooperation with S. Fillatreau, several hits were found that induced IL-10 in B cells.

Thus, exploiting the portfolio of natural tolerance and inhibitory mechanisms of the immune system might provide novel approaches for the therapy of autoimmunity and chronic inflammation in diseases such as rheumatoid arthritis.

Selected Publications

Gupta, S., J. Pfeil, S. Kumar, C. Poulsen, U. Lauer, A. Hamann, U. Hoffmann, and R. Haag. 2015. Tolerogenic modulation of the immune response by oligoglycerol- and polyglycerol-Peptide conjugates. Bioconjugate chemistry 26: 669-679.

Pink, M., B. A. Ratsch, M. Mardahl, P. Durek, J. K. Polansky, M. Karl, R. Baumgrass, S. Wallner, C. Cadenas, K. Gianmoena, S. Floess, W. Chen, K. Nordstroem, S. Tierling, S. Olek, J. Walter, A. Hamann, and U. Syrbe. 2016. Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene. J Immunol 197: 3406-3414.

Durek, P., K. Nordstrom, G. Gasparoni, A. Salhab, C. Kressler, M. de Almeida, S. Frischbutter, the DEEP Consortium, U. Syrbe, A. Radbruch, J. Walter, A. Hamann, and J. K. Polansky. 2016. Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development. Immunity 45: 1148-1161.

Szilagyi, B. A., J. Triebus, C. Kressler, M. d. Almeida, S. Tierling, P. Durek, M. Mardahl, A. Szilagyi, S. Floess, J. Huehn, U. Syrbe, J. Walter, J. K. Polansky, and A. Hamann. 2017. Gut memories do not fade: Epigenetic regulation of lasting gut  oming receptor expression in CD4+ memory T cell. Mucosal Immunol. Advance online publication 15 February 2017. doi:10.1038/mi.2017.7

Kenngott, E. E., J. Pfeil, U. Hoffmann, U. Lauer, A. A. Kuehl, A. Rigby, A. Pernthaner, and A. Hamann. 2017. Facilitated Peptide Transport via the Mucosal Epithelium: Impact on Tolerance induction. Front Immunol. 8:216. doi: 10.3389/mmu.2017.00216.

Members

Group leader
Prof. Dr. rer. nat. Alf Hamann

Scientists
Dr. Pawel Durek
Dr. Stefan Frischbutter
Dr. Ute Hoffmann
Dr. Matthias Pink
Dr. Julia Polansky-Biskup
PD Dr. Uta Syrbe*
* Med. Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie Charité – CBF Berlin

Ph.D. students
Dipl. Biol. Elisabeth Kenngott (2016: Dr.rer.nat)
M. Sci. Biochem. Christopher Kressler
Dipl. Biol. Matthias Kröger
M. Sci. Mol. Biol. Maibritt Mardahl (2016: Dr.rer. nat)
Dipl. Biol. Jennifer Pfeil (2016: Dr.rer.nat)
Dipl. Biochem. Julia Triebus (2015: Dr.rer.nat)

Diploma/Bachelor/Master-Students
Melanie de Almeida
Siska Wilantri
Sabrina Schüngel
Olga Trupp
Wojciech Leszczynski
Lydia Verlaat

Technical assistance
Uta Lauer
René Maier

Cooperation partners

Germany
Celares GmbH, Berlin

Dr. Ho-Ryun Chung - Max Planck Institut für Molekulare Genetik, Berlin

Dr. Thomas Hanke, Evotec AG, Hamburg

Prof. Rainer Haag, Freie Universität, Institut für Chemie und Biochemie, Berlin

Prof. Susanne Hartmann, Dr. Svenja Steinfelder, Institut für Immunologie, Veterinärmedizin, FU Berlin

Prof. Andreas Herrmann, Humboldt-Universität, Inst. für Biologie; Molekulare Biophysik, Berlin

Prof. Jochen Hühn, Dr. Stefan Flöß, Helmholtz-Zentrum für Infektionsforschung, Braunschweig

Dr. Jens Peter von Kries, Dr. Marc Nazaré, Dr. Edgar Specker, Screening Unit, Medicinal Chemistry, Leibniz-Institut für Molekulare Pharmakologie (FMP); Berlin

Dr. Anja Kühl, Dr. Ulrike Erben, Charité, iPATH Berlin and RCIS, Berlin

Dr. Thomas Manke, Einheit f. Informatik, MPI f. Immunbiologie und Epigenetik, Freiburg

Prof. Thomas Schneider, Dr. Verena Moos, Prof. Dr. Britta Siegmund, Charité , Inst. f. Gastroenterologie, Infektiologie und Rheumatologie, Berlin

Prof. Tim Sparwasser and Dr. Matthias Lochner, Twin Core, Institut für Infektionsimmunologie, MH Hannover

Dr. Marcel Schulz, High-throughput Genomics & Systems Biology, MPI f. Informatik, Saarbrücken

Prof. Joachim L. Schultze, Genomforschung und Immunregulation. LIMES-Institut, UniversitätBonn

Prof. Jörn Walter, Universität des Saarlandes, FB Genetik, Saarbrücken

Others
Prof. Gudrun Debes, Prof. Chris Hunter, University of Pennsylvania, Dept. Pathobiology, Philadelphia, USA

Dr. Sara Atkisons, Dept. Diabetes Complications Res., Global Research, Novo Nordisk A/S, and Dept. Vet. Disease Biol., Univ. Copenhagen, Denmark.

Dr. Anton Pernthaner, AG Research Ltd., Hopkirk Research Institute, Neuseeland

Dr. Olaf Rötzschke, Singapore Immunology Network, Agency for Science, Technology and Research, Singapore

Weitere Partner des DEEP Konsortiums (www.deutsches-epigenom-programm.de)

Prof. Dr. rer. nat. Alf Hamann

Deutsches Rheuma-Forschungszentrum Berlin
Experimental Rheumatology
Charitéplatz 1
10117 Berlin
Gemany

Phone +49 (0)30 28460 655
Fax +49 (0)30 28460-603
hamann@drfz.de

Keywords
Epigenetics
T memory cells
Regulatory T cells
Immunoregulation
Immunotherapy