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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 1

Aim2 is induced in chronic (6-month) gastric inflammation, and its deficiency exacerbates SPEM.

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Aim2 is induced in chronic (6-month) gastric inflammation, and its defic...
(A) Microarray heatmap of gastric Aim2 mRNA expression in 6-month H. felis–infected stomach and gastric-tissue specific IFN-γ–overexpressing mice. NTG, nontransgenic. (B) RT-qPCR of Aim2 mRNA expression in 6-month H. felis–infected WT versus Aim2–/– stomachs relative to uninfected. HPRT, hypoxanthine phosphoribosyltransferase. (C) Representative H&E image of 6-month H. felis–infected WT versus Aim2–/– gastric mucosa. Scale bar: 100 μm. (D) Stomach weight, normalized to total body weight, of 6-month H. felis–infected WT versus Aim2–/– mouse stomachs relative to uninfected. (E) Representative immunofluorescence image for quantifying SPEM, by labeling gastric mucous neck cells (Griffonia simplicifolia II; GSII; shown in red), chief cells (intrinsic factor, shown in green), parietal cells (H+/K+-ATPase, shown in gray), and cell nuclei (DAPI, shown in blue). Scale bar: 200 μm (all images). (F) Morphometric analysis showing SPEM quantification by percentage area. SPEM was quantified by GSII and trefoil factor 2 coexpression in ×20 field views. (G) Morphometric analysis of parietal cell number per 1000 μm2 of gastric mucosal tissue. Each data point represents 1 mouse. Error bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Data were compared using one-way ANOVA with Dunnet’s (parametric) multiple comparison tests.

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