T cell–derived interferon-γ programs stem cell death in immune-mediated intestinal damage
Autor: | Daniel J. Chandra, Ross L. Levine, Caroline A. Lindemans, Noah F. Shroyer, Sean M. Devlin, S. Middendorp, Joris Bos, Margaret O'Connor, Alan M. Hanash, M. Kleppe, Shuichiro Takashima, Anastasiya Egorova, Paola Vinci, Chen Liu, Maria Laura Martin, Suze A. Jansen, Anna Mertelsmann, Jason Kuttiyara, Yuan-Hung Lo, Richard Kolesnick, Ya-Yuan Fu, Emily H. Cheng, Marco Calafiore |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Programmed cell death T-Lymphocytes T cell Immunology Biology digestive system Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Immune system Intestinal mucosa Interferon medicine Animals Intestinal Mucosa Cell Death Stem Cells General Medicine Intestinal epithelium 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Paneth cell Cancer research Stem cell medicine.drug |
Zdroj: | Science Immunology. 4 |
ISSN: | 2470-9468 |
Popis: | 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. |
Databáze: | OpenAIRE |
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