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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 5

Dendritic cell–specific deletion of Aim2 does not recapitulate the gastric CD8+ T cell phenotype elicited by global Aim2 deficiency.

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Dendritic cell–specific deletion of Aim2 does not recapitulate the gastr...
(A) RT-qPCR of IFNB1, IL36A, and TNFSF10 in CD11cCre Aim2fl/fl versus Aim2fl/fl BMDCs transfected with gastric metaplastic DNA versus untransfected control. Each data point represents 1 experiment. Error bars represent the mean ± SEM. *P < 0.05. (B) Representative FACS analyses and quantification of gastric CD4+ and CD8+ T cells from H. felis–infected CD11cCre Aim2fl/fl versus Aim2fl/fl relative to uninfected Aim2fl/fl. (C) Representative CD3 immunohistochemistry (brown) of CD11cCre Aim2fl/fl versus Aim2fl/fl 6-month H. felis–infected gastric mucosa. Scale bar: 150 μm. (D) RT-qPCR analyses of gastric CD3 mRNA expression in 6-month H. felis–infected CD11cCre Aim2fl/fl versus Aim2fl/fl stomachs relative to uninfected controls. Each data point represents 1 mouse. N.S., not significant. Data were compared using one-way ANOVA with Dunnet’s (parametric) multiple comparison tests.

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