Essential role of IFN-γ in T cell–associated intestinal inflammation
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette
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Research Article Gastroenterology Inflammation

Essential role of IFN-γ in T cell–associated intestinal inflammation

Abstract

Paneth cells contribute to small intestinal homeostasis by secreting antimicrobial peptides and constituting the intestinal stem cell (ISC) niche. Certain T cell–mediated enteropathies are characterized by extensive Paneth cell depletion coincident with mucosal destruction and dysbiosis. In this study, mechanisms of intestinal crypt injury have been investigated by characterizing responses of mouse intestinal organoids (enteroids) in coculture with mouse T lymphocytes. Activated T cells induced enteroid damage, reduced Paneth cell and Lgr5+ ISC mRNA levels, and induced Paneth cell death through a caspase-3/7–dependent mechanism. IFN-γ mediated these effects, because IFN-γ receptor–null enteroids were unaffected by activated T cells. In mice, administration of IFN-γ induced enteropathy with crypt hyperplasia, villus shortening, Paneth cell depletion, and modified ISC marker expression. IFN-γ exacerbated radiation enteritis, which was ameliorated by treatment with a selective JAK1/2 inhibitor. Thus, IFN-γ induced Paneth cell death and impaired regeneration of small intestinal epithelium in vivo, suggesting that IFN-γ may be a useful target for treating defective mucosal regeneration in enteric inflammation.

Authors

Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette

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Figure 11

IFN-γ increases the radiosensitivity of intestinal epithelial tissue.

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IFN-γ increases the radiosensitivity of intestinal epithelial tissue. (A...
(A) Schematic depiction of TBI, and IFN-γ and ruxolitinib administration in mice. After TBI, mice received syngeneic bone marrow transplantation (BMT) to rescue from bone marrow death on day 0. Survival (B), body weight as a percentage of initial weight (C), and clinical severity scores (D) from 2 independent experiments were combined, and data are shown as mean values ± SEM (IFN-γ alone group, n = 6; TBI alone group, n = 6; TBI + IFN-γ group, n = 10; TBI + IFN-γ + ruxolitinib group, n= 10). (E–M) Histology of mouse ileal sections 48 hours after TBI. H&E staining of ileum sections from mice receiving TBI (E), TBI + IFN-γ (F), or TBI + IFN-γ + ruxolitinib (G). (H–M) Confocal imaging of Lgr5-EGFP-ires-creERT2 mouse ileum sections. Immunofluorescence staining of cryptdin-1 (red, H-M), Lgr5-GFP+ (green, white arrows, H-J), Olfm4 (green) and DAPI (blue) (K-M) for mice that received TBI (H and K), TBI + IFN-γ (I and L), or TBI + IFN-γ + ruxolitinib (J and M). The results are representative of 2 separate experiments and illustrate the reduction in crypt numbers and the loss and absence of Paneth cells and rapidly cycling ISCs in ileum of TBI + IFN-γ–treated mice (F, I, and L). Scale bars: 100 μm.