ORIGINAL RESEARCH article

Front. Immunol.

Sec. T Cell Biology

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1601008

CREB REGULATES FOXP3 + ST-2 + TREGS WITH ENHANCED IL-10 PRODUCTION

Provisionally accepted
Sudheendra Hebbar SubramanyamSudheendra Hebbar Subramanyam1Judit Turyne HriczkoJudit Turyne Hriczko1Saskia SchulzSaskia Schulz1Thomas LookThomas Look2,3Tannaz GoodarziTannaz Goodarzi1Tim ClarnerTim Clarner4Miriam ScheldMiriam Scheld5Markus KippMarkus Kipp6Eva VerjansEva Verjans1Svenja BoellSvenja Boell1Christopher NeullensChristopher Neullens1Ivan CostaIvan Costa7Zhijian LiZhijian Li7Lin GanLin Gan8Bernd DeneckeBernd Denecke8Angela SchippersAngela Schippers1Stefan FloessStefan Floess9Jochen HuehnJochen Huehn9Edgar SchmittEdgar Schmitt10Tobias BoppTobias Bopp10Hermann WasmuthHermann Wasmuth11Ron WinogradRon Winograd11Rudi BeyaertRudi Beyaert12,13Bart LambrechtBart Lambrecht12,14Martin ZenkeMartin Zenke2,3Norbert WagnerNorbert Wagner1Kim OhlKim Ohl15Klaus TenbrockKlaus Tenbrock1,16*
  • 1Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
  • 2Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, North Rhine-Westphalia, Germany
  • 3Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, University Hospital, Aachen, Germany
  • 4Institute of Neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen Univeristy, Aachen, Germany
  • 5Institute of neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
  • 6Institute of Anatomy, Medical university of Rostock, Rostock, Germany
  • 7Institute for Computational Genomics, IZKF, RWTH Aachen University, Aachen, Germany
  • 8Genomics Facility, Interdisciplinary Center for Clinical Research Aachen (IZKF Aachen), RWTH Aachen University, Aachen, Germany
  • 9Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany, Braunschweig, Germany
  • 10Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
  • 11Luiusenhospital Aachen, Deptartment of Medicine, Aachen, Germany
  • 12VIB Center for Inflammation Research, Ghent, Belgium
  • 13Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
  • 14Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
  • 15Institute of Immunology, University Hospital RWTH Aachen, Aachen, Germany
  • 16Division of Pediatric Rheumatology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

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Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, enhanced numbers of Tregs are found in vivo in spleen, lung and colon. These Tregs display a reduced Foxp3 expression, but enhanced expression of the IL-33 receptor (ST-2), IL-10, IL-13, and CREM. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in CD4 T cell mediated transfer colitis in an IL-10 dependent manner. Mechanistically CREB fulfils dual roles in Tregs: (1) it promotes Foxp3 expression under Steady state conditions and (2) in cooperation with CREM, CREB restricts chromatin accessibility at the ST2 locus, thereby modulating IL-33 driven immune responses. This dual regulation balances FoxP3-dependent Treg stability with IL-10 mediated suppression of inflammation. Brief summary: Mice with a Foxp3-specific knockout of CREB display enhanced expression of IL-13, IL-10, ST-2 and CREM, which prevents gut inflammation

Keywords: IL-33, Foxp3, IL-10, cAMP, CREM

Received: 27 Mar 2025; Accepted: 04 Jun 2025.

Copyright: © 2025 Hebbar Subramanyam, Turyne Hriczko, Schulz, Look, Goodarzi, Clarner, Scheld, Kipp, Verjans, Boell, Neullens, Costa, Li, Gan, Denecke, Schippers, Floess, Huehn, Schmitt, Bopp, Wasmuth, Winograd, Beyaert, Lambrecht, Zenke, Wagner, Ohl and Tenbrock. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Klaus Tenbrock, Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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