Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance, there is limited understanding of how immune-mediated damage affects ISCs and their niche. We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T cell-mediated injury models. Although imaging revealed few T cells near the stem cell compartment in healthy mice, donor T cells infiltrating the intestinal mucosa after allogeneic bone marrow transplantation (BMT) primarily localized to the crypt region lamina propria. Further modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon coculture with activated T cells, and screening of effector pathways identified interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. IFNγ induced JAK1- and STAT1-dependent toxicity, initiating a proapoptotic gene expression program and stem cell death. BMT with IFNγ-deficient donor T cells, with recipients lacking the IFNγ receptor (IFNγR) specifically in the intestinal epithelium, and with pharmacologic inhibition of JAK signaling all resulted in protection of the stem cell compartment. In addition, epithelial cultures with Paneth cell-deficient organoids, IFNγR-deficient Paneth cells, IFNγR-deficient ISCs, and purified stem cell colonies all indicated direct targeting of the ISCs that was not dependent on injury to the Paneth cell niche. Dysregulated T cell activation and IFNγ production are thus potent mediators of ISC injury, and blockade of JAK/STAT signaling within target tissue stem cells can prevent this T cell-mediated pathology.

中文翻译：

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T细胞衍生的干扰素-γ程序在免疫介导的肠道损伤中导致干细胞死亡。

尽管肠干细胞（ISC）对于上皮维持很重要，但对免疫介导的损伤如何影响ISC及其利基的了解仍然有限。我们发现，干细胞区室损伤是同种反应性和自身反应性肠道免疫病理学的共同特征，可减少ISC并损害其在T细胞介导的损伤模型中的恢复。尽管成像显示健康小鼠的干细胞室附近几乎没有T细胞，但同种异体骨髓移植（BMT）后浸入肠粘膜的供体T细胞主要位于隐窝固有层。用离体上皮培养物进行的进一步建模表明，与活化T细胞共培养后，ISC耗竭并损害了人类以及鼠类器官的存活，效应通路的筛选确定干扰素-γ（IFNγ）是ISC区室损伤的主要介质。IFNγ诱导JAK1和STAT1依赖性毒性，启动凋亡基因表达程序并导致干细胞死亡。BMT具有IFNγ缺陷的供体T细胞，受体在肠道上皮细胞中缺乏IFNγ受体（IFNγR），并且具有JAK信号传导的药理抑制作用，所有这些都可以保护干细胞区室。此外，具有Paneth细胞缺陷的类器官，IFNγR缺陷的Paneth细胞，IFNγR缺陷的ISC和纯化的干细胞集落的上皮培养物都表明了ISC的直接靶向性，而这并不依赖于Paneth细胞生态位的损伤。因此，T细胞活化失调和IFNγ产生是ISC损伤的有效介体，