Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury
Intestinal stem cells (ISCs) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses, such as interferon γ (IFNγ)-mediated killing. In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation, we observed IFNγ expression by intestinal T<sub>reg</sub> cells. T<sub>reg</sub> cells leverage combined IFNγ and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, T<sub>reg</sub> cells or the combined addition of recombinant IFNγ and IL-10 promoted the regeneration of organoids after irradiation, and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo. The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγ and Wnt-like properties of IL-10. While IFNγ rapidly induced epithelial proliferation, it depleted the pool of ISCs in vitro. Only the combination of IFNγ and IL-10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time. Our results reveal a context-dependent role of inflammatory signaling in ISCs, through which T<sub>reg</sub> cells promote epithelial repair following therapy-induced injury.
Authors
- Katja Steiger (ORCID: https://orcid.org/0000-0002-7269-5433)
- Markus Tschurtschenthaler (ORCID: https://orcid.org/0000-0002-0060-4790)
- Caroline N. Walther
- Lena Klostermeier
- Maike Büttner‐Herold (ORCID: https://orcid.org/0000-0002-9974-6683)
- Thomas Engleitner (ORCID: https://orcid.org/0000-0002-7989-681X)
- Sebastian Jarosch (ORCID: https://orcid.org/0000-0002-2908-8590)
- Petra Hoffmann (ORCID: https://orcid.org/0009-0003-3541-6196)
- Laura Lansink Rotgerink
- Ernst Holler (ORCID: https://orcid.org/0000-0003-2295-2187)
- Daniel Wolff (ORCID: https://orcid.org/0000-0001-7015-3190)
- Erik Thiele Orberg (ORCID: https://orcid.org/0000-0003-1969-8261)
- Rupert Öllinger (ORCID: https://orcid.org/0000-0002-2292-5982)
- Hendrik Poeck (ORCID: https://orcid.org/0000-0002-0836-2095)
- Michael Rehli (ORCID: https://orcid.org/0000-0003-3992-932X)
- Markus Feuerer (ORCID: https://orcid.org/0000-0003-4261-3764)
- Oliver Kepp (ORCID: https://orcid.org/0000-0002-6081-9558)
- Sarah Diederich (ORCID: https://orcid.org/0000-0002-1546-492X)
- Florian C. Bassermann (ORCID: https://orcid.org/0000-0003-4435-2609)
- Stephanie Elisabeth Combs (ORCID: https://orcid.org/0000-0002-6934-2864)
- Dirk Hans Busch (ORCID: https://orcid.org/0000-0001-8713-093X)
- Sascha Göttert (ORCID: https://orcid.org/0000-0001-5177-3909)
- Marianne Remke (ORCID: https://orcid.org/0000-0002-1363-4737)
- Paul Heinrich (ORCID: https://orcid.org/0000-0002-6149-2083)
- Nicholas Strieder (ORCID: https://orcid.org/0000-0003-1183-1099)
- Sophie M. Nefzger (ORCID: https://orcid.org/0000-0002-9571-5783)
- Julius Fischer (ORCID: https://orcid.org/0000-0002-6951-3416)
- Simon Heidegger (ORCID: https://orcid.org/0000-0001-6394-5130)
- Guido Kroemer (ORCID: https://orcid.org/0000-0002-9334-4405)
- Eva Vonbrunn (ORCID: https://orcid.org/0000-0003-0418-0267)
- Sakhila Ghimire
- Matthias Edinger (ORCID: https://orcid.org/0000-0003-2889-2533)
- Roland Rad (ORCID: https://orcid.org/0000-0002-6849-9659)
- Claudia Gebhard (ORCID: https://orcid.org/0000-0002-5459-8381)
- Gabriel Eisenkolb (ORCID: https://orcid.org/0000-0002-0717-5861)
- Laura Joachim (ORCID: https://orcid.org/0000-0003-2132-7013)
- Vincent R. Timnik
- Kaiji Fan (ORCID: https://orcid.org/0000-0003-4310-4515)
- Maximilian Giller
- Wolfgang Herr
- Omer Khalid
- Nicole A Schmid (ORCID: https://orcid.org/0009-0002-7461-7321)
- Maria Drießlein
Institutions
- Inserm (FR)
- German Cancer Research Center (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Institut Universitaire de France (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- University Hospital Regensburg (DE)
- Leibniz Association (DE)
- Sorbonne Université (FR)
- Universitätsklinikum Erlangen (DE)
- Centre de Recherche des Cordeliers (FR)
- Universitäres Kinderwunschzentrum Lübeck (DE)
- Hôpital Européen Georges-Pompidou (FR)
- Hôpital Européen (FR)
- Institute of Clinical Cancer Research (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- Leibniz Institute for Immunotherapy
- Tumkur University (IN)
- Technical University of Munich (DE)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41392-025-02476-5
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Melanoma Research Alliance
- Association pour la Recherche sur le Cancer
- Wilhelm Sander-Stiftung
- European Commission
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- José Carreras Leukämie-Stiftung
- Deutsche Krebshilfe
- Institut National Du Cancer
- HORIZON EUROPE European Innovation Council