Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury

Summary Intestinal stem cells (ISC) 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 gut damage and biopsies from patients having undergone allo-hematopoietic stem cell transplantation, we observed IFNy expression by intestinal T reg cells. T reg 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 reg cells or the combined addition of recombinant IFNγ and IL-10 promote the regeneration of organoids after irradiation. Exposure of organoids to Wnt- or EGF-free culture conditions revealed distinct growth factor-like properties of IFNγ and IL-10. While IFNγ induced epithelial proliferation and differentiation, combined addition of IFNγ and IL-10 led to balanced proliferation, ensuring ISC maintenance. Our results uncover a context-dependent role of inflammatory signaling in ISC, through which T reg cells promote epithelial repair.