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 signalling³, and mice completely lacking Irf2⁴ 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.

肠道干细胞（ISC）位于隐窝基部，可以微调其自我更新和分化的平衡^1,2，但是调节该平衡的生理机制仍然未知。在这里，我们描述了一种转录调节因子，它通过限制ISC分化成分泌细胞谱系来保留其干性。干扰素调节因子2（IRF2）负调节干扰素信号传导³，并且完全缺乏Irf2 ⁴或在其肠道上皮细胞中具有选择性Irf2缺失的小鼠的隐窝Lgr5 ^hi ISCs明显少于对照小鼠。尽管在稳定状态下肠上皮细胞的完整性不受损害。Irf2缺陷型小鼠，5-氟尿嘧啶引起的损伤后肠道上皮的再生受到严重损害。同样，小剂量聚（I：C）的长期治疗或淋巴细胞性脉络膜脑膜炎病毒克隆13（LCMV C13）^5的慢性感染导致野生型小鼠的ISC功能下降。相比之下，在Irf2 ^-/-以及LCMV C13感染的野生型小鼠的隐窝底部发现了大量未成熟Paneth细胞积累，表明过量的干扰素信号传导将ISC导向分泌细胞的命运。总的来说，我们的发现表明，受调节的干扰素信号传导通过限制分泌细胞的分化而保留了ISC的干性。