Regulated IFN Signalling Preserves the Stemness of Intestinal Stem Cells by Restricting Differentiation into Secretory-Cell Lineages

Intestinal stem cells (ISCs) are located at the crypt base and fine-tune the balance of their self-renewal and differentiation 1 , 2 , but the physiological mechanism involved in regulating that balance remains unknown. Here we describe a transcriptional regulator that preserves the stemness of ISCs by restricting their differentiation into secretory-cell lineages. Interferon regulatory factor 2 (IRF2) negatively regulates interferon signalling 3 , and mice completely lacking Irf2 4 or with a selective Irf2 deletion in their intestinal epithelial cells have significantly fewer crypt Lgr5 hi ISCs than control mice. Although the integrity of intestinal epithelial cells was unimpaired at steady state in Irf2- deficient mice, regeneration of their intestinal epithelia after 5-fluorouracil-induced damage was severely impaired. Similarly, extended treatment with low-dose poly(I:C) or chronic infection of lymphocytic choriomeningitis virus clone 13 (LCMV C13) 5 caused a functional decline of ISCs in wild-type mice. In contrast, massive accumulations of immature Paneth cells were found at the crypt base of Irf2 −/− as well as LCMV C13-infected wild-type mice, indicating that excess interferon signalling directs ISCs towards a secretory-cell fate. Collectively, our findings indicate that regulated interferon signalling preserves ISC stemness by restricting secretory-cell differentiation.