CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa
KW Cook, DP Letley, RJM Ingram, E Staples… - Gut, 2014 - gut.bmj.com
Gut, 2014•gut.bmj.com
Background Helicobacter 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. Objective To identify the homing receptors
involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the
relevant chemokine responses. Design Gastric biopsy samples and peripheral blood were
donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified …
with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs
into the gastric mucosa is therefore important. Objective To identify the homing receptors
involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the
relevant chemokine responses. Design Gastric biopsy samples and peripheral blood were
donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified …
Background
Helicobacter 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.
Objective
To identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses.
Design
Gastric 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.
Results
CCL20, 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.
Conclusions
As 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.
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