title: CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa.
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.
  
  
  METHODS
  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(+)CD25(hi) 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.
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Cook
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Letley
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: Richard J M
authors.initials: RJ
authors.lastname: Ingram
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Staples
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: Helle
authors.initials: H
authors.lastname: Skjoldmose
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Atherton
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Robinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D054418:Chemokine CCL20 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000276:immunology*; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010437:Peptic Ulcer / Q000276:immunology* / Q000382:microbiology; D054399:Receptors, CCR6 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D006113:United Kingdom; D055815:Young Adult
chemical_list: C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D018925:Chemokines; D054399:Receptors, CCR6
keywords: CHEMOTAXIS; HELICOBACTER PYLORI; MUCOSAL IMMUNOLOGY; T LYMPHOCYTES