Research ArticleMUCOSAL IMMUNOLOGY

T cell–derived interferon-γ programs stem cell death in immune-mediated intestinal damage

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Science Immunology  06 Dec 2019:
Vol. 4, Issue 42, eaay8556
DOI: 10.1126/sciimmunol.aay8556

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Protecting intestinal stem cells

As the intestinal epithelium is replaced every week, maintenance of this tissue requires rapid self-renewal that is driven by intestinal stem cells. This homeostasis is disrupted in a number of settings, including allogeneic bone marrow transplantation. After allogeneic bone marrow transplantation, allogeneic T cells often attack and kill intestinal cells in an interferon-γ (IFNγ)–dependent manner. Here, Takashima et al. have used both in vivo transplant models and in vitro organoid systems to define the targets of IFNγ in the intestine, and they found that IFNγ directly targets intestinal stem cells. They further demonstrate that JAK/STAT inhibitors can be used to protect the intestinal stem cell compartment from T cell–mediated damage in this setting. See the related Focus by Kretzschmar and Clevers.

Abstract

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.

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