H. pylorimodulates DC functions via T4SS/TNF\u03b1/p38-dependent SOCS3 expression

Abstract

BackgroundHelicobacter pylori (H. pylori) is a gram-negative bacterium thatchronically infects approximately 50% of the world’s human population. While inmost cases the infection remains asymptomatic, 10% of infected individualsdevelop gastric pathologies and 1–3% progress to gastric cancer. AlthoughH. pylori induces severe inflammatoryresponses, the host’s immune system fails to clear the pathogen and H. pylori can persist in the human stomach fordecades. As suppressor of cytokine signaling (SOCS) proteins are importantfeedback regulators limiting inflammatory responses, we hypothesized thatH. pylori could modulate the host’simmune responses by inducing SOCS expression.MethodsThe phenotype of human monocyte-derived DCs (moDCs) infected withH. pylori was analyzed by flow cytometryand multiplex technology. SOCS expression levels were monitored by qPCR andsignaling studies were conducted by means of Western blot. For functionalstudies, RNA interference-based silencing of SOCS1–3 and co-cultures with CD4+ Tcells were performed.ResultsWe show that H. pylori positivegastritis patients express significantly higher SOCS3, but not SOCS1 andSOCS2, levels compared to H. pylori negative patients. Moreover, infection ofhuman moDCs with H. pylori rapidly inducesSOCS3 expression, which requires the typeIV secretion system (T4SS), release of TNFα, and signaling via the MAP kinasep38, but appears to be independent of TLR2, TLR4, MEK1/2 and STAT proteins.Silencing of SOCS3 expression in moDCs priorto H. pylori infection resulted in increasedrelease of both pro- and anti-inflammatory cytokines, upregulation of PD-L1, anddecreased T-cell proliferation.ConclusionsThis study shows that H. pyloriinduces SOCS3 via an autocrine loop involving the T4SS and TNFα and p38signaling. Moreover, we demonstrate that high levels of SOCS3 in DCs dampenPD-L1 expression on DCs, which in turn drives T-cell proliferation.CCmc62eD1mGkZDfDAmputCVideo