Helicobacter pylori (H. pylori) is a gram-negative bacterium that chronically infects approximately 50% of the world’s human population. While in most cases the infection remains asymptomatic, 10% of infected individuals develop gastric pathologies and 1–3% progress to gastric cancer. Although H. pylori induces severe inflammatory responses, the host’s immune system fails to clear the pathogen and H. pylori can persist in the human stomach for decades. As suppressor of cytokine signaling (SOCS) proteins are important feedback regulators limiting inflammatory responses, we hypothesized that H. pylori could modulate the host’s immune responses by inducing SOCS expression. The phenotype of human monocyte-derived DCs (moDCs) infected with H. pylori was analyzed by flow cytometry and multiplex technology. SOCS expression levels were monitored by qPCR and signaling studies were conducted by means of Western blot. For functional studies, RNA interference-based silencing of SOCS1–3 and co-cultures with CD4+ T cells were performed. We show that H. pylori positive gastritis patients express significantly higher SOCS3, but not SOCS1 and SOCS2, levels compared to H. pylori negative patients. Moreover, infection of human moDCs with H. pylori rapidly induces SOCS3 expression, which requires the type IV secretion system (T4SS), release of TNFα, and signaling via the MAP kinase p38, but appears to be independent of TLR2, TLR4, MEK1/2 and STAT proteins. Silencing of SOCS3 expression in moDCs prior to H. pylori infection resulted in increased release of both pro- and anti-inflammatory cytokines, upregulation of PD-L1, and decreased T-cell proliferation. This study shows that H. pylori induces SOCS3 via an autocrine loop involving the T4SS and TNFα and p38 signaling. Moreover, we demonstrate that high levels of SOCS3 in DCs dampen PD-L1 expression on DCs, which in turn drives T-cell proliferation.

中文翻译：

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幽门螺杆菌通过 T4SS/TNFα/p38 依赖的 SOCS3 表达调节 DC 功能

幽门螺杆菌（H. pylori）是一种革兰氏阴性细菌，可长期感染世界上大约 50% 的人口。虽然在大多数情况下感染保持无症状，但 10% 的感染者会出现胃病，1-3% 会发展为胃癌。尽管 H. pylori 会引起严重的炎症反应，但宿主的免疫系统无法清除病原体，因此 H. pylori 可以在人体胃中持续存在数十年。由于细胞因子信号传导 (SOCS) 蛋白的抑制因子是限制炎症反应的重要反馈调节因子，我们假设幽门螺杆菌可以通过诱导 SOCS 表达来调节宿主的免疫反应。通过流式细胞术和多重技术分析了感染幽门螺杆菌的人单核细胞衍生 DCs (moDCs) 的表型。SOCS 表达水平通过 qPCR 监测，信号研究通过蛋白质印迹进行。对于功能研究，进行了基于 RNA 干扰的 SOCS1-3 沉默以及与 CD4+ T 细胞的共培养。我们表明，与 H. pylori 阴性患者相比，H. pylori 阳性胃炎患者表达显着更高的 SOCS3，但不是 SOCS1 和 SOCS2。此外，幽门螺杆菌感染人类 moDCs 会迅速诱导 SOCS3 表达，这需要 IV 型分泌系统 (T4SS)、TNFα 的释放和通过 MAP 激酶 p38 的信号传导，但似乎独立于 TLR2、TLR4、MEK1/ 2 和 STAT 蛋白。在幽门螺杆菌感染之前，moDCs 中 SOCS3 表达的沉默导致促炎和抗炎细胞因子的释放增加、PD-L1 的上调和 T 细胞增殖的减少。该研究表明，幽门螺杆菌通过涉及 T4SS 和 TNFα 以及 p38 信号传导的自分泌环诱导 SOCS3。此外，我们证明 DC 中高水平的 SOCS3 抑制了 DC 上的 PD-L1 表达，这反过来又驱动了 T 细胞增殖。