CCL20/CCR6-mediated migration of regulatory T cells to theHelicobacter pylori-infected human gastric mucosa

Abstract

BackgroundHelicobacter pylori-induced peptic ulceration is less likely to occur in patients with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs into the gastric mucosa is therefore important.ObjectiveTo identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses.DesignGastric biopsy samples and peripheral blood were donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified gastric biopsy chemokine concentrations. Flow cytometry was used to characterise homing receptors on CD4+CD25hi Tregs. H pylori wild-type and isogenic mutants were used to investigate the signalling mechanisms behind CCL20 and IL-8 induction in gastric epithelial cell lines. Transwell assays were used to quantify Treg migration towards chemokines in vitro.ResultsCCL20, CXCL1-3 and IL-8 concentrations were significantly increased in gastric biopsy samples from H pylori-infected patients. CCR6 (CCL20 receptor), CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) were expressed by a higher proportion of peripheral blood Tregs in infected patients. Most gastric Tregs expressed these receptors. H pylori induced CCL20 production by gastric epithelial cells via cag pathogenicity island (cagPAI)-dependent NF-κB signalling. Foxp3+, but not Foxp3−, CD4 cells from infected mice migrated towards recombinant CCL20 in vitro.ConclusionsAs well as increasing Treg numbers, H pylori infection induces a change in their characteristics. Expression of CCR6, CXCR1 and CXCR2 probably enables their migration towards CCL20 and IL-8 in the infected gastric mucosa. Such qualitative changes may also explain how H pylori protects against some extragastric inflammatory disorders.

Dual role ofHelicobacterandCampylobacterspecies in IBD: a systematic review and meta-analysis

“…Furthermore, it has been recently shown that H. pylori infection downregulates the expression of the T cell co-inhibitory molecule B7-H1 in gastric epithelial cells in a CagA-dependent manner, which might contribute to the hyporesponsiveness of CD4(+) effector T cells and accumulation of Tregs 94. Also, H. pylori infection has been shown to induce the production of the chemokine CCL20 in gastric epithelial cells via cag pathogenicity island-dependent nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, a phenomenon believed to be involved in Tregs homing to the gastric mucosa as the majority of Tregs express its receptor CCR6 95 . H. pylori strains expressing CagA represent 60–70% of Western strains and approximately 100% of East-Asian strains 96.…”

Helicobacter pylori interferes with leukocyte migration via the outer membrane protein HopQ and via CagA translocation

“…The activity of HP-NAP might also be involved in priming of T cells to a proinflammatory phenotype (Amedei et al, 2006). Infiltrating T lymphocytes have been reported to be recruited to the gastric mucosa via CCL20 binding to their CCR6 chemokine receptors (Cook et al, 2014;Wu et al, 2007), via L-selectin receptors (CD62L) binding to peripheral lymph node addressin (PNAd) (Kobayashi et al, 2004), and via ␣ 4 ␤ 7 integrins, which are known to bind to MAdCAM-1 adhesion molecules expressed by endothelial cells in the gastrointestinal tract (Michetti et al, 2000;Quiding-Järbrink et al, 2001).…”

<b><i>Helicobacter pylori</i></b> Inhibits Dendritic Cell Maturation via Interleukin-10-Mediated Activation of the Signal Transducer and Activator of Transcription 3 Pathway

“…These STAT3-deficient DCs are more potent activators of T cells and have a high capacity to induce Th1 responses [28]. Indeed, several studies have determined that H. pylori -stimulated DCs promote the development of Tregs in vitro [4,5,6,27] and an increase in infiltrating Tregs has been detected in murine models of infection [4,5] as well as in the gastric mucosa of infected humans [33]. Of interest, an increase in Tregs is detected in the gastric mucosa of H. pylori -infected subjects with gastric adenocarcinoma in comparison with H. pylori -mediated chronic gastritis or dysplasia [34].…”