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Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells
Mohamad El-Zaatari, … , Marilia Cascalho, John Y. Kao
Mohamad El-Zaatari, … , Marilia Cascalho, John Y. Kao
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(5):e94035. https://doi.org/10.1172/jci.insight.94035.
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Research Article Gastroenterology

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells

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Abstract

Development of gastric cancer is often preceded by chronic inflammation, but the immune cellular mechanisms underlying this process are unclear. Here we demonstrated that an inflammasome molecule, absent in melanoma 2 (Aim2), was upregulated in patients with gastric cancer and in spasmolytic polypeptide-expressing metaplasia of chronically Helicobacter felis–infected stomachs in mice. However, we found that Aim2 was not necessary for inflammasome function during gastritis. In contrast, Aim2 deficiency led to an increase in gastric CD8+ T cell frequency, which exacerbated metaplasia. These gastric CD8+ T cells from Aim2–/– mice were found to have lost their homing receptor expression (sphingosine-1-phosphate receptor 1 [S1PR1] and CD62L), a feature of tissue-resident memory T cells. The process was not mediated by Aim2-dependent regulation of IFN-β or by dendritic cell–intrinsic Aim2. Rather, Aim2 deficiency contributed to an increased production of CXCL16 by B cells, which could suppress S1PR1 and CD62L in CD8+ T cells. This study describes a potentially novel function of Aim2 that regulates CD8+ T cell infiltration and retention within chronically inflamed solid organ tissue. This function operates independent of the inflammasome, IFN-β, or dendritic cells. We provide evidence that B cells can contribute to this mechanism via CXCL16.

Authors

Mohamad El-Zaatari, Shrinivas Bishu, Min Zhang, Helmut Grasberger, Guoqing Hou, Henry Haley, Brock Humphries, Li-Jyun Syu, Andrzej A. Dlugosz, Kathy Luker, Gary D. Luker, Kathryn Eaton, Nobuhiko Kamada, Marilia Cascalho, John Y. Kao

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Figure 4

Deficiency in type I IFN signaling does not reverse the increase in gastric CD8+ T cells observed in H.

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Deficiency in type I IFN signaling does not reverse the increase in gast...
felis–infected Aim2–/– mice, but rather exacerbates pathology. (A) RT-qPCR of Ifnb1 (IFN-β gene) mRNA expression in Aim2–/– versus WT bone marrow–derived macrophages (BMDCs) transfected with metaplastic gastric DNA from 6-month H. felis–infected stomach, relative to untransfected controls. Each data point represents 1 experiment. (B) RT-qPCR of IFN-β gene mRNA expression in 6-month H. felis–infected Aim2–/– versus WT stomachs, relative to uninfected controls. Each data point represents 1 mouse. (C) Representative CD3 immunohistochemistry (brown) of WT, Aim2–/–, IFNAR1–/–, and Aim2–/– IFNAR1–/– 6-month H. felis–infected gastric mucosa. Scale bar: 100 μm. (D) RT-qPCR analyses of gastric CD3 mRNA expression in 6-month H. felis–infected WT, Aim2–/–, IFNAR1–/–, and Aim2–/– IFNAR1–/– stomachs relative to uninfected controls. (E) Representative H&E image of 6-month H. felis–infected Aim2–/– versus Aim2–/– IFNAR1–/– gastric mucosa. Scale bars: 300 μm (left), 250 μm (right). The white arrows denote dysplastic gastric glands that have invaded the gastric submucosa. Error bars represent the mean ± SEM. N.S., not significant; *P < 0.05; **P < 0.01; ***P < 0.001. Data were compared using one-way ANOVA with Dunnet’s (parametric) multiple comparison tests (A and B). Data were compared using one-way ANOVA with Dunnet’s (nonparametric) multiple comparison tests (C).

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