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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

Authors

Katherine W. Cook

Richard J.M. Ingram

Emily Staples

Helle Skjoldmose

JOHN ATHERTON john.atherton@nottingham.ac.uk
Pro Vice Chancellor and Dean



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