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

Cook, Katherine W.; Letley, Darren P.; Ingram, Richard J.M.; Staples, Emily; Skjoldmose, Helle; Atherton, John C; Robinson, Karen

Abstract

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.

Citation

Cook, K. W., Letley, D. P., Ingram, R. J., Staples, E., Skjoldmose, H., Atherton, J. C., & Robinson, K. (2014). CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa. Gut, 63(10), 1550-1559. https://doi.org/10.1136/gutjnl-2013-306253

• Journal Article Type: Article
• Acceptance Date: Dec 15, 2013
• Online Publication Date: Jan 16, 2014
• Publication Date: Oct 31, 2014
• Deposit Date: Oct 15, 2018
• Publicly Available Date: Oct 15, 2018
• Journal: Gut
• Print ISSN: 0017-5749
• Electronic ISSN: 1468-3288
• Publisher: BMJ Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 63
• Issue: 10
• Pages: 1550-1559
• DOI: https://doi.org/10.1136/gutjnl-2013-306253
• Public URL: https://nottingham-repository.worktribe.com/output/1165028
• Publisher URL: https://gut.bmj.com/content/63/10/1550
• Contract Date: Oct 15, 2018