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

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.

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease

“…In part, Th1 and Th2 cells cause tissue-specific damage to the intestine and lungs, respectively (50). During GVHD, T cell-derived IFN-γ also mediates apoptosis of intestinal stem cells and related epithelial tissue damage (46). Novel strategies to target donor Th1 responses currently exist and are largely driven by p40 cytokine neutralization or inhibition of relevant downstream receptor signal transduction (41-43, 51, 52).…”

“…However, the ratio of Tregs (CD4 + , CD127 -, CD25 + , Foxp3 + ) to activated Tconvs (CD4 + , CD127 + , CD25 + ) (41) was significantly increased in mice that received CD83 CAR T cells ( Figure 6G). Th1 cells and IFN-γ contribute to GVHD pathogenesis (45,46). Importantly, mice treated with CD83 CAR T cells exhibited a profound reduction in human CD4 + IFN-γ + Th1 cells ( Figure 6, H and I).…”

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

“…A recent study showed that fibroblasts could secrete extracellular vesicles with Wnt and EGF activity, thereby rescuing Wnt-or EGF-deficient organoid growth [49]. Endothelial cells when inducing apoptosis did not affect intestine epithelial cell number change [50]. Glucagonlike peptide 2 (GLP-2) receptor, a product of neurons, could positively regulate epithelial growth [51].…”

Integrated urine proteomics and renal single-cell genomics identify an IFN-γ response gradient in lupus nephritis

“…Importantly, this molecule induces the formation of germinal centers, T follicular helper cell development, and class switch in B cells (32). In the gut, IFN-γ mediates the death of intestinal stem cells, suggesting that a similar mechanism may have implications for irreversible kidney damage and fibrosis (33). In humans, encouragingly positive phase II trials showed the efficacy of blocking the IFN-γ pathway in extrarenal lupus (34)(35)(36).…”