H. pylori modulates DC functions via T4SS/TNFα/p38-dependent SOCS3 expression.

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Video Abstract.