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August 28, 2024 preprint Open access Aachen paper

CREB and CREM reciprocally regulate expression of ST2 in Tregs and mediate the balance between type 1 and type 2 immune responses

DOI: 10.22541/au.172489829.93821221/v1 Full text (OA) OpenAlex

Abstract

Background: Regulatory T cells (T regs ) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains T reg identity. The cAMP response element binding protein CREB is suggested to regulate T reg function and expression, however detailed analysis of CREB function in Tregs is lacking. Methods: Mice with a Foxp3-specific knockout of CREB were generated, phenotypically characterized using flow cytometry and serological testing and Tregs were subjected to whole transcriptome, TSDR methylation and ATACseq analysis. An ovalbumin induced asthma model and a T cell transfer colitis model were performed. Results: CREB deficient T regs expand in vivo but show a reduced Foxp3 expression combined with an enhanced expression of ST2, IL-5, IL-13, IL-10, and CREM, while GATA3 was not altered. Enhanced prevalence of ST2 positive Tregs was found in different organs. CREB deficient T regs were suppressive in vitro and prevented disease activity in the Th1 model of T cell mediated transfer colitis in an IL-10 dependent way while Foxp3 CRE CREB fl/fl mice showed enhanced ovalbumin mediated asthma severity and spontaneous IgE production. While TSDR methylation was unchanged in CREB deficient T regs , deficiency of CREB alters chromatin accessibility at the ST2, IL13 and CREM locus. Additional genetic CREM deficiency reversed the ST2 phenotype and worsened colitis. Conclusion: Our data suggest that the balance between CREB and CREM expression is important for the regulation of ST2 expression in T regs and for the balance between type 1 and type 2 immune responses.

Authors 28

  1. Sudheendra Hebbar Subramanyam Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  2. Judit Turyne Hriczko Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  3. Thomas A. Look Aachen Department of Pediatrics Department of Cell Biology Institute for Biomedical Engineering

    RWTH Aachen University · Universitätsklinikum Aachen · Jülich Aachen Research Alliance · University of Rostock · Universitätsmedizin Rostock

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

    Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany

    Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, University Hospital, Aachen, Germany

    JARA Institut Molecular Neuroscience and Neuroimaging

    Universitatsmedizin Rostock Institut fur Anatomie

  4. Tannaz Goodarzi Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  5. Tim Clarner Aachen Faculty of Medicine Department of Cell Biology Institute for Biomedical Engineering Institute of Neuroanatomy and JARA-BRAIN

    RWTH Aachen University · Universitätsklinikum Aachen · Jülich Aachen Research Alliance

    Affiliation as printed

    JARA Institut Molecular Neuroscience and Neuroimaging

    Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, University Hospital, Aachen, Germany

    Institute of Neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen University

    Rheinisch-Westfalische Technische Hochschule Aachen

  6. Miriam Scheld Aachen Faculty of Medicine Department of Cell Biology Institute for Biomedical Engineering Institute of Neuroanatomy and JARA-BRAIN

    RWTH Aachen University · Universitätsklinikum Aachen · Jülich Aachen Research Alliance

    Affiliation as printed

    JARA Institut Molecular Neuroscience and Neuroimaging

    Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, University Hospital, Aachen, Germany

    Institute of Neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen University

    Rheinisch-Westfalische Technische Hochschule Aachen

  7. Markus Kipp Aachen

    RWTH Aachen University · University of Rostock · Universitätsmedizin Rostock

    Affiliation as printed

    Universitatsmedizin Rostock Institut fur Anatomie

    Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany

    Institute of Anatomy, Medical University of Rostock, Rostock, Germany

    Rheinisch Westfalische Technische Hochschule Aachen Schreibzentrum

  8. Eva Verjans Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  9. Svenja Böll Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  10. Christopher T. Neullens Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  11. Ivan G. Costa Aachen Faculty of Medicine Institute of Neuroanatomy and JARA-BRAIN Instutute for Computational Genomics

    RWTH Aachen University · Helmholtz Centre for Infection Research

    Affiliation as printed

    Rheinisch-Westfalische Technische Hochschule Aachen

    Helmholtz-Zentrum fur Infektionsforschung Abteilung Genregulierung und Differenzierung

    Institute of Neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen University

    Instutute for Computational Genomics, IZKF, RWTH Aachen University

  12. Zhijian Li Aachen Faculty of Medicine Institute of Neuroanatomy and JARA-BRAIN Instutute for Computational Genomics

    RWTH Aachen University · Helmholtz Centre for Infection Research

    Affiliation as printed

    Rheinisch-Westfalische Technische Hochschule Aachen

    Helmholtz-Zentrum fur Infektionsforschung Abteilung Genregulierung und Differenzierung

    Institute of Neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen University

    Instutute for Computational Genomics, IZKF, RWTH Aachen University

  13. Lin Gan Aachen Interdisciplinary Centre for Clinical Research Aachen Genomics Facility

    RWTH Aachen University · Johannes Gutenberg University Mainz · University of Rostock · Universitätsmedizin Rostock

    Affiliation as printed

    Rheinisch Westfalische Technische Hochschule Aachen Schreibzentrum

    Genomics Facility, Interdisciplinary Center for Clinical Research Aachen (IZKF Aachen), RWTH Aachen University, Aachen, Germany

    Institute of Anatomy, Medical University of Rostock, Rostock, Germany

    Johannes Gutenberg Universitat Mainz

  14. Bernd Denecke Aachen Interdisciplinary Centre for Clinical Research Aachen Genomics Facility

    RWTH Aachen University · Johannes Gutenberg University Mainz · University of Rostock · Universitätsmedizin Rostock

    Affiliation as printed

    Rheinisch Westfalische Technische Hochschule Aachen Schreibzentrum

    Genomics Facility, Interdisciplinary Center for Clinical Research Aachen (IZKF Aachen), RWTH Aachen University, Aachen, Germany

    Institute of Anatomy, Medical University of Rostock, Rostock, Germany

    Johannes Gutenberg Universitat Mainz

  15. Angela Schippers Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  16. Stefan Floess Aachen Luisenhospital Aachen Instutute for Computational Genomics

    RWTH Aachen University · Luisenhospital Aachen · Helmholtz Centre for Infection Research

    Affiliation as printed

    Helmholtz-Zentrum fur Infektionsforschung Abteilung Genregulierung und Differenzierung

    Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germa-ny

    Instutute for Computational Genomics, IZKF, RWTH Aachen University

    Luisenhospital Aachen

  17. Jochen Huehn Aachen Luisenhospital Aachen Instutute for Computational Genomics

    RWTH Aachen University · Luisenhospital Aachen · Helmholtz Centre for Infection Research

    Affiliation as printed

    Helmholtz-Zentrum fur Infektionsforschung Abteilung Genregulierung und Differenzierung

    Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germa-ny

    Instutute for Computational Genomics, IZKF, RWTH Aachen University

    Luisenhospital Aachen

  18. Edgar Schmitt Aachen Interdisciplinary Centre for Clinical Research Aachen Genomics Facility

    RWTH Aachen University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Vlaams Instituut voor Biotechnologie

    Affiliation as printed

    Johannes Gutenberg Universitat Mainz

    Genomics Facility, Interdisciplinary Center for Clinical Research Aachen (IZKF Aachen), RWTH Aachen University, Aachen, Germany

    Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Ger-many

    Vlaams Instituut voor Biotechnologie Elewaut Unit Moleculaire immunologie en ontstekingseenheid

  19. Tobias Bopp Aachen Interdisciplinary Centre for Clinical Research Aachen Genomics Facility

    RWTH Aachen University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Vlaams Instituut voor Biotechnologie

    Affiliation as printed

    Johannes Gutenberg Universitat Mainz

    Genomics Facility, Interdisciplinary Center for Clinical Research Aachen (IZKF Aachen), RWTH Aachen University, Aachen, Germany

    Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Ger-many

    Vlaams Instituut voor Biotechnologie Elewaut Unit Moleculaire immunologie en ontstekingseenheid

  20. Hermann E. Wasmuth Aachen Luisenhospital Aachen Luiusenhospital Aachen Dept. of Medicine

    Luisenhospital Aachen · Helmholtz Centre for Infection Research

    Affiliation as printed

    Luisenhospital Aachen

    Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germa-ny

    Luiusenhospital Aachen, Dept. of Medicine, Aachen, Germany

  21. Ron Winograd Aachen Luisenhospital Aachen Luiusenhospital Aachen Dept. of Medicine

    Luisenhospital Aachen · Helmholtz Centre for Infection Research

    Affiliation as printed

    Luisenhospital Aachen

    Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germa-ny

    Luiusenhospital Aachen, Dept. of Medicine, Aachen, Germany

  22. Rudi Beyaert

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Ghent University · VIB-UGent Center for Inflammation Research · Vlaams Instituut voor Biotechnologie

    Affiliation as printed

    Vlaams Instituut voor Biotechnologie Elewaut Unit Moleculaire immunologie en ontstekingseenheid

    Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Ger-many

    VIB Center for Inflammation Research, Ghent, Belgium

  23. Bart N. Lambrecht

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Ghent University Hospital · VIB-UGent Center for Inflammation Research · Vlaams Instituut voor Biotechnologie

    Affiliation as printed

    Vlaams Instituut voor Biotechnologie Elewaut Unit Moleculaire immunologie en ontstekingseenheid

    Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium

    Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Ger-many

    VIB Center for Inflammation Research, Ghent, Belgium

  24. Peter Boor Aachen Institute of Pathology Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

    Institute of Pathology, RWTH Aachen, University Hospital, Aachen, Germany

  25. Martin Zenke Aachen Department of Pediatrics Department of Cell Biology Institute for Biomedical Engineering

    RWTH Aachen University · Universitätsklinikum Aachen · Jülich Aachen Research Alliance · University of Rostock · Universitätsmedizin Rostock

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

    Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany

    Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, University Hospital, Aachen, Germany

    JARA Institut Molecular Neuroscience and Neuroimaging

    Universitatsmedizin Rostock Institut fur Anatomie

  26. Norbert Wagner Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  27. Kim Ohl Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

  28. Klaus Tenbrock corresponding Aachen Department of Pediatrics

    RWTH Aachen University · Universitätsklinikum Aachen · University of Bern · University Hospital of Bern · University Children’s Hospital Bern

    Affiliation as printed

    Universitatsklinikum Aachen

    Dept. of Pediatrics, RWTH Aachen University

    Division of Pediatric Rheumatology, Department of Pediatrics, Inselspital, Bern University Hospital, Uni-versity of Bern, Switzerland

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References 30