Division of Gastroenterology and Hepatology, Department of Internal Medicine.
Department of Radiology, Microbiology and Immunology, and Biomedical Engineering.
JCI Insight. 2020 Mar 12;5(5):94035. doi: 10.1172/jci.insight.94035.
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.
胃癌的发生通常伴随着慢性炎症，但这一过程中的免疫细胞机制尚不清楚。在这里，我们证明了缺失黑色素瘤 2（Aim2）的炎症小体分子在胃癌患者和慢性感染幽门螺杆菌的胃痉挛多肽表达化生小鼠中上调。然而，我们发现 Aim2 在胃炎期间对于炎症小体功能不是必需的。相反，Aim2 缺陷导致胃 CD8+T 细胞频率增加，进而加剧化生。我们发现来自 Aim2-/-小鼠的这些胃 CD8+T 细胞失去了归巢受体表达（鞘氨醇-1-磷酸受体 1 [S1PR1]和 CD62L），这是组织驻留记忆 T 细胞的特征。这个过程不是由依赖 Aim2 的 IFN-β调节或树突状细胞内在的 Aim2 介导的。相反，Aim2 缺陷导致 B 细胞产生更多的 CXCL16，从而抑制 CD8+T 细胞中的 S1PR1 和 CD62L。本研究描述了 Aim2 调节慢性炎症实体组织中 CD8+T 细胞浸润和保留的潜在新功能。该功能独立于炎症小体、IFN-β或树突状细胞。我们提供的证据表明，B 细胞可以通过 CXCL16 来参与这一机制。
