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 7

IFN-γ mediates enteroid damage induced by splenocyte activation.

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IFN-γ mediates enteroid damage induced by splenocyte activation. (A) WT ...
(A) WT or IFN-γ receptor–KO (IFN-γRKO, KO) enteroids in coculture with WT splenocytes with or without activation using anti-CD3/anti-CD28 beads. (B) Damage scores of WT or KO enteroids in coculture with control or activated WT splenocytes. Data are representative of 2 independent experiments and shown as mean ± SEM, with n = 100 enteroids per group. (C) qRT-PCR analyses to quantify lineage-specific and apoptosis marker mRNAs in WT or IFN-γRKO enteroids in coculture with control or activated WT splenocytes for 4 days. Data are representative of 2 independent experiments and shown as mean ± SEM (n = 5 independent wells). Dunnett’s multiple comparisons test was used to compare each group with the WT control group. *P < 0.05, **P < 0.01, ***P < 0.001. Scale bar: 200 μm.