TY  - JOUR
AU  - Fischer, Julius C
AU  - Göttert, Sascha
AU  - Giller, Maximilian
AU  - Heinrich, Paul
AU  - Fan, Kaiji
AU  - Khalid, Omer
AU  - Walther, Caroline N
AU  - Drießlein, Maria
AU  - Nefzger, Sophie M
AU  - Eisenkolb, Gabriel
AU  - Timnik, Vincent R
AU  - Jarosch, Sebastian
AU  - Klostermeier, Lena
AU  - Engleitner, Thomas
AU  - Strieder, Nicholas
AU  - Gebhard, Claudia
AU  - Diederich, Sarah
AU  - Schmid, Nicole A
AU  - Lansink Rotgerink, Laura
AU  - Joachim, Laura
AU  - Ghimire, Sakhila
AU  - Vonbrunn, Eva
AU  - Büttner-Herold, Maike
AU  - Remke, Marianne
AU  - Steiger, Katja
AU  - Öllinger, Rupert
AU  - Rad, Roland
AU  - Wolff, Daniel
AU  - Feuerer, Markus
AU  - Hoffmann, Petra
AU  - Edinger, Matthias
AU  - Rehli, Michael
AU  - Tschurtschenthaler, Markus
AU  - Kepp, Oliver
AU  - Kroemer, Guido
AU  - Thiele Orberg, Erik
AU  - Combs, Stephanie E
AU  - Herr, Wolfgang
AU  - Bassermann, Florian
AU  - Busch, Dirk H
AU  - Holler, Ernst
AU  - Heidegger, Simon
AU  - Poeck, Hendrik
TI  - Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury.
JO  - Signal transduction and targeted therapy
VL  - 10
IS  - 1
SN  - 2095-9907
CY  - London
PB  - Macmillan Publishers, part of Springer Nature
M1  - DKFZ-2025-02622
SP  - 384
PY  - 2025
AB  - 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 Treg cells. Treg 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, Treg 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 Treg cells promote epithelial repair following therapy-induced injury.
KW  - Animals
KW  - T-Lymphocytes, Regulatory: immunology
KW  - T-Lymphocytes, Regulatory: pathology
KW  - Mice
KW  - Humans
KW  - Interferon-gamma: genetics
KW  - Interferon-gamma: immunology
KW  - Interleukin-10: genetics
KW  - Interleukin-10: immunology
KW  - Intestines: immunology
KW  - Intestines: pathology
KW  - Intestines: radiation effects
KW  - Intestines: injuries
KW  - Organoids: immunology
KW  - Inflammation: immunology
KW  - Inflammation: pathology
KW  - Inflammation: genetics
KW  - Intestinal Mucosa: immunology
KW  - Intestinal Mucosa: pathology
KW  - Hematopoietic Stem Cell Transplantation
KW  - Stem Cells: immunology
KW  - Stem Cells: pathology
KW  - Interferon-gamma (NLM Chemicals)
KW  - Interleukin-10 (NLM Chemicals)
KW  - IL10 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41290566
DO  - DOI:10.1038/s41392-025-02476-5
UR  - https://inrepo02.dkfz.de/record/306581
ER  -