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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 3

Aim2 deficiency leads to downregulation of gastric CD8+ T cell homing receptors characteristic of tissue-resident memory T cells.

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Aim2 deficiency leads to downregulation of gastric CD8+ T cell homing re...
(A) Microarray heatmap of homing receptor S1PR1, SELL (CD62L), LY6C2 (LY6C), and CD69 expression in isolated gastric CD8+ versus CD4+ T cells. Mse, mouse. (B) RT-qPCR of S1PR1 homing receptor mRNA expression in isolated gastric CD8+ T cells (versus CD8– control populations) from 6-month H. felis–infected WT versus Aim2–/– stomachs. Each data point represents 1 mouse. Error bars represent the mean ± SEM. *P < 0.05. (C) Immunofluorescence analysis of CD8+ cells (green), epithelial cells (E-cadherin, red), and nuclei (DAPI, blue) in 6-month H. felis–infected Aim2–/– versus WT stomachs. Arrows indicate intraepithelial and stromal localizations of gastric CD8+ cells in the Aim2–/– gastric mucosa. Scale bar: 20 μm. (D) Higher magnification inset from C: coexpression of CD8 (green) and E-cadherin (red) in the chronically infected Aim2–/– gastric mucosa. (E) Coexpression of CD8 (green, upper) and CD103 (red, lower) in the chronically infected Aim2–/– gastric mucosa, as denoted by white arrows. Epithelial cell E-cadherin is labeled in blue. Data were compared using one-way ANOVA with Dunnet’s (parametric) multiple comparison tests.

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