Regenerative Immunology

Objectives

The hematopoietic system and the immune system in particular are of utmost relevance for regenerative medicine. First, molecular mechanisms of hematopoietic lineage decisions are paradigmatic for cellular reprogramming and differentiation of pluripotent as well as other stem cells. Second, the generation of immunological tolerance is paramount to prevent rejection of transplanted tissues and biomaterials. Finally, regeneration of the immune system itself after myeloablative therapy and hematopoietic stem cell transplantation frequently remains inefficient and, thus, requires extensive study both with respect to basic mechanisms as well as the development of treatment strategies in translational approaches.

More than 50 years after its inception bone-marrow transplantation to treat lethal diseases such as leukemias/lymphomas remains associated with a prolonged phase of immunodeficiency due to failure of efficient regeneration of the adaptive immune system. It is our long-term goal to better understand the fundamental processes of lymphoid cell development in order to ultimately harness this knowledge to develop targeted therapies for immune regeneration

Research Focus

Our primary research interest is in lineage decisions during lymphoid development, with particular focus on T-lineage differentiation. T cells develop in the thymus, but ultimately derive from hematopoietic stem cells in the bone marrow. However, both the nature of thymus seeding precursors and the mechanisms governing T-lineage commitment remain largely elusive. Our research group is investigating the spatio-temporal regulation of extrathymic and intrathymic T cell differentiation. Using novel mouse models and state-of-the-art imaging technology, we aim to identify thymus-seeding T cell precursors as well as the molecular mechanisms that regulate lymphoid lineage decisions in bone marrow and thymus. We are also studying human hematopoietic precursors in order to gain insight into the efficacy of T lineage reconstitution of different human T cell precursor populations.

A second major reseach focus is devoted to understanding how regulatory non-coding RNAs, so-called microRNAs, control hematopoiesis and T-cell development in particular. We hope that elucidation of this novel layer of regulation of T cell development will help to better understand diseases, such as leukemia and autoimmunity, and to be able to improve immune regeneration after hematopoietic stem cell transplantation.

Collaborations

  • Hans Bakker, JRG Stem Cell Glycans, Institute for Cellular Chemistry, MHH 
  • Axel Schambach, JRG Hematopoetic Cell Therapy, Experimental Hematology, MHH
  • Gudrun Göhring, Institute for Cellular and Molecular Pathology, MHH 
  • Matthias Eder, Michaela Scherr, Clinic for Haematology, Haemostaseology and Oncology, MHH 
  • Toni Cathomen, Research Group Cell and Gene Therapy, Universitätsklinikum Freiburg 
  • Achim Gossler, Institute for Molecular Biology, MHH 
  • Reinhold Förster, Institute for Immunology, MHH 
  • Immo Prinz, Institute for Immunology, MHH
  • Oliver Pabst, Institute for Immunology, MHH 
  • Harald von Boehmer, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA 
  • John Tsang, Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, NIH, Bethesda, USA 
  • Ronald Naumann, Transgenic Core Facility, Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden 
  • Ulrich Kalinke, Twincore, Hannover 
  • Elmar Jaeckel, Department of Gastroenterology, Hepatology, Endocrinology, MHH 
  • Jens Bohne, Institute for Virology, MHH 
  • Christoph Klein, Ludwig-Maximilians-Univeristät , Munich 
  • Sebastian Herzog, Freiburg University 
  • Adrian Liston, KU Leuven, Belgium 

Awards

  • Hannover Biomedical Research School PhD Prize 2011 – Namita Saran
  • Emmy-Noether Research Group (DFG) since March 2008

Teaching

  • Lectures and lab courses in Master’s Programs “Biochemistry” and “Biomedicine”
  • Lectures for Medical students (3rd year)
  • Lectures lab courses, and seminars in PhD programs “Infection Biology”, “Regenerative Sciences”, and “Molecular Medicine”

Publications

2013 - ongoing

2017

Krueger A, Zietara N, Lyszkiewicz M. T Cell Development by the Numbers. Trends in immunology. 2017;38(2):128-39.

Fleige H, Forster R. Induction and Analysis of Bronchus-Associated Lymphoid Tissue. Methods in molecular biology. 2017;1559:185-98.

2016

Lee CW, Wohlan K, Dallmann I, Forster R, Ganser A, Krueger A, Scherr M, Eder M, Koenecke C. miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation. Journal of immunology. 2016;196(9):3927-34.

Blume J, Zur Lage S, Witzlau K, Georgiev H, Weiss S, Lyszkiewicz M, Zietara N, Krueger A. Overexpression of Valpha14Jalpha18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1. Immunology and cell biology. 2016;94(8):741-6.

2015

Zietara N, Lyszkiewicz M, Puchalka J, Witzlau K, Reinhardt A, Forster R, Pabst O, Prinz I, Krueger A. Multicongenic fate mapping quantification of dynamics of thymus colonization. The Journal of experimental medicine. 2015;212(10):1589-601.

Sandrock I, Zietara N, Lyszkiewicz M, Oberdorfer L, Witzlau K, Krueger A, Prinz I. MicroRNA-181a/b-1 Is Not Required for Innate gammadelta NKT Effector Cell Development. PloS one. 2015;10(12):e0145010.

Zietara N, Lyszkiewicz M, Puchalka J, Witzlau K, Reinhardt A, Forster R, Pabst O, Prinz I, Krueger A. Multicongenic Fate Mapping Quantification of Dynamics of Thymus Colonization. J Exp Med. 2015;212(10):1589-601.

Regelin M, Blume J, Pommerencke J, Vakilzadeh R, Witzlau K, Lyszkiewicz M, Zietara N, Saran N, Schambach A, Krueger A. Responsiveness of Developing T Cells to Il-7 Signals Is Sustained by Mir-17 Approximately 92. J Immunol. 2015;195(10):4832-40. Epub 2015/10/18.

Lyszkiewicz M, Zietara N, Fohse L, Puchalka J, Diestelhorst J, Witzlau K, Prinz I, Schambach A, Krueger A. Limited Niche Availability Suppresses Murine Intrathymic Dendritic-Cell Development from Noncommitted Progenitors. Blood. 2015;125(3):457-64. Epub 2014/11/21.

2014

Zietara N, Lyszkiewicz M, Krueger A, Weiss S. B-Cell Modulation of Dendritic-Cell Function: Signals from the Far Side. Eur J Immunol. 2014;44(1):23-32.

Ugur M, Schulz O, Menon MB, Krueger A, Pabst O. Resident Cd4+ T Cells Accumulate in Lymphoid Organs after Prolonged Antigen Exposure. Nat Commun. 2014;5:4821.

Schulz O, Ugur M, Friedrichsen M, Radulovic K, Niess JH, Jalkanen S, Krueger A, Pabst O. Hypertrophy of Infected Peyer's Patches Arises from Global, Interferon-Receptor, and Cd69-Independent Shutdown of Lymphocyte Egress. Mucosal Immunol. 2014;7(4):892-904.

Braune EB, Schuster-Gossler K, Lyszkiewicz M, Serth K, Preusse K, Madlung J, Macek B, Krueger A, Gossler A. S/T Phosphorylation of Dll1 Is Required for Full Ligand Activity in Vitro but Dispensable for Dll1 Function in Vivo During Embryonic Patterning and Marginal Zone B Cell Development. Mol Cell Biol. 2014;34(7):1221-33. Epub 2014/01/23.

2013

Zietara N, Lyszkiewicz M, Witzlau K, Naumann R, Hurwitz R, Langemeier J, Bohne J, Sandrock I, Ballmaier M, Weiss S, Prinz I, Krueger A. Critical Role for Mir-181a/B-1 in Agonist Selection of Invariant Natural Killer T Cells. Proc Natl Acad Sci U S A. 2013;110(18):7407-12.

Zietara N, Lyszkiewicz M, Puchalka J, Pei G, Gutierrez MG, Lienenklaus S, Hobeika E, Reth M, Martins dos Santos VA, Krueger A, Weiss S. Immunoglobulins Drive Terminal Maturation of Splenic Dendritic Cells. Proc Natl Acad Sci U S A. 2013;110(6):2282-7.

2006 - 2012

2012

Saran N, Pommerencke J, Witzlau K, Regelin M, Krueger A. Extra-Thymic Physiological T Lineage Progenitor Activity Is Exclusively Confined to Cells Expressing Either Cd127, Cd90, or High Levels of Cd117. PLoS One. 2012;7(2):e30864. Epub 2012/02/23.

Haas JD, Ravens S, Duber S, Sandrock I, Oberdorfer L, Kashani E, Chennupati V, Fohse L, Naumann R, Weiss S, Krueger A, Forster R, Prinz I. Development of Interleukin-17-Producing Gammadelta T Cells Is Restricted to a Functional Embryonic Wave. Immunity. 2012;37(1):48-59. Epub 2012/07/10.

2011

Zietara N, Lyszkiewicz M, Krueger A, Weiss S. Icos-Dependent Stimulation of Nkt Cells by Marginal Zone B Cells. Eur J Immunol. 2011;41(11):3125-34.

Surdziel E, Cabanski M, Dallmann I, Lyszkiewicz M, Krueger A, Ganser A, Scherr M, Eder M. Enforced Expression of Mir-125b Affects Myelopoiesis by Targeting Multiple Signaling Pathways. Blood. 2011;117(16):4338-48.

Lyszkiewicz M, Witzlau K, Pommerencke J, Krueger A. Chemokine Receptor Cx3cr1 Promotes Dendritic Cell Development under Steady-State Conditions. Eur J Immunol. 2011;41(5):1256-65.

Krueger A. A Missing Link in Thymic Dendritic Cell Development. Eur J Immunol. 2011;41(8):2145-7.

Haas JD, Nistala K, Petermann F, Saran N, Chennupati V, Schmitz S, Korn T, Wedderburn LR, Forster R, Krueger A, Prinz I. Expression of Mirnas Mir-133b and Mir-206 in the Il17a/F Locus Is Co-Regulated with Il-17 Production in Alphabeta and Gammadelta T Cells. PLoS One. 2011;6(5):e20171. Epub 2011/06/04.

2010

Saran N, Lyszkiewicz M, Pommerencke J, Witzlau K, Vakilzadeh R, Ballmaier M, von Boehmer H, Krueger A. Multiple Extrathymic Precursors Contribute to T-Cell Development with Different Kinetics. Blood. 2010;115(6):1137-44.

Krueger A, Willenzon S, Lyszkiewicz M, Kremmer E, Forster R. Cc Chemokine Receptor 7 and 9 Double-Deficient Hematopoietic Progenitors Are Severely Impaired in Seeding the Adult Thymus. Blood. 2010;115(10):1906-12.

2009

Weber C, Krueger A, Munk A, Bode C, Van Veldhoven PP, Graler MH. Discontinued Postnatal Thymocyte Development in Sphingosine 1-Phosphate-Lyase-Deficient Mice. J Immunol. 2009;183(7):4292-301.

2008

Kreslavsky T, Garbe AI, Krueger A, von Boehmer H. T Cell Receptor-Instructed Alphabeta Versus Gammadelta Lineage Commitment Revealed by Single-Cell Analysis. J Exp Med. 2008;205(5):1173-86.

2007

Krueger A, von Boehmer H. Identification of a T Lineage-Committed Progenitor in Adult Blood. Immunity. 2007;26(1):105-16.

Junt T, Schulze H, Chen Z, Massberg S, Goerge T, Krueger A, Wagner DD, Graf T, Italiano JE, Jr., Shivdasani RA, von Andrian UH. Dynamic Visualization of Thrombopoiesis within Bone Marrow. Science. 2007;317(5845):1767-70. Epub 2007/09/22.

2006

Krueger A, Garbe AI, von Boehmer H. Phenotypic Plasticity of T Cell Progenitors Upon Exposure to Notch Ligands. J Exp Med. 2006;203(8):1977-84. Epub 2006/07/19.

Garbe AI, Krueger A, Gounari F, Zuniga-Pflucker JC, von Boehmer H. Differential Synergy of Notch and T Cell Receptor Signaling Determines Alphabeta Versus Gammadelta Lineage Fate. J Exp Med. 2006;203(6):1579-90.

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