CREB regulates Foxp3+ST-2+ TREGS with enhanced IL-10 production
<i>Foxp3<sup>cre</sup>CREB<sup>fl/fl</sup></i> mice showed increased frequencies of T<sub>regs</sub> (CD25+/Foxp3+) in thymus, spleen and peripheral lymph nodes and in nonlymphoid organs including lung and colon, but decreased Foxp3 expression at the single cell level. Despite decreased Foxp3 expression, enhanced expression of the IL- 33 receptor (ST-2), IL-10, IL-13, and CREM was observed. CREB deficient T<sub>regs</sub> were highly suppressive <i>in vitro</i> and prevented disease activity in a CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in T<sub>regs</sub>: (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.
Authors
- Martin Zenke (ORCID: https://orcid.org/0000-0002-1107-3251)
- Christopher T. Neullens (ORCID: https://orcid.org/0000-0002-7940-4977)
- Bernd Denecke
- Lin Gan (ORCID: https://orcid.org/0000-0001-6731-2971)
- Eva Verjans (ORCID: https://orcid.org/0000-0003-3806-9583)
- Jochen Huehn (ORCID: https://orcid.org/0000-0001-8071-1379)
- Stefan Floess (ORCID: https://orcid.org/0000-0001-9904-4094)
- Tobias Bopp (ORCID: https://orcid.org/0000-0002-3232-8065)
- Tim Clarner (ORCID: https://orcid.org/0000-0002-8180-7775)
- Judit Turyne Hriczko
- Miriam Scheld (ORCID: https://orcid.org/0000-0002-5070-970X)
- Svenja Böll
- Thomas Look (ORCID: https://orcid.org/0000-0001-5410-6220)
- Ivan G. Costa (ORCID: https://orcid.org/0000-0003-2890-8697)
- Saskia J. Schulz
- Markus Kipp (ORCID: https://orcid.org/0000-0001-5043-9052)
- Angela Schippers (ORCID: https://orcid.org/0000-0003-2132-7486)
- Tannaz Goodarzi
- Edgar Schmitt (ORCID: https://orcid.org/0000-0002-6343-2375)
- Sudheendra Hebbar Subramanyam
- Bart N. Lambrecht (ORCID: https://orcid.org/0000-0003-4376-6834)
- Rudi Beyaert (ORCID: https://orcid.org/0000-0002-5704-582X)
- Kim Ohl
- Klaus Tenbrock (ORCID: https://orcid.org/0000-0002-3566-227X)
- Zhijian Li (ORCID: https://orcid.org/0000-0002-1523-1333)
- Norbert Wagner
- Ron Winograd
- Hermann E. Wasmuth
Institutions
- HOGENT University of Applied Sciences and Arts (BE)
- Johannes Gutenberg University Mainz (DE)
- University Hospital of Bern (CH)
- Ghent University Hospital (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- Ghent University (BE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Integrated Oncology (United States) (US)
- Luisenhospital Aachen (DE)
- Helmholtz Centre for Infection Research (DE)
- Jülich Aachen Research Alliance (DE)
- VIB-UGent Center for Inflammation Research (BE)
- Westfälische Hochschule (DE)
- University of Rostock (DE)
- FH Aachen (DE)
Publication Details
- Journal
- Frontiers in Immunology
- Published
- 2025-07-24
- DOI
- https://doi.org/10.3389/fimmu.2025.1601008
- Citations
- 2
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Deutsche Forschungsgemeinschaft
- RWTH Aachen University
- Medizinische Fakultät, RWTH Aachen University