title: Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase.
abstract: OBJECTIVE
  Helicobacter pylori colonizes the human gastric mucosa of >50% of the world's population. Most of the patients have no overt clinical symptoms. However, the infection is invariably associated with the development of active chronic gastritis, leading in some cases to the development of peptic ulcer disease, distal gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. In contrast to most other pathogens, infection with H pylori persists lifelong, but reasons for the persistence remain obscure. CD4-positive T cells are crucial for bacterial elimination but are inhibited by H pylori. We aimed to identify the factor responsible for suppression of T-cell response and characterize this inhibitory effect on a cellular and molecular level.
  
  
  METHODS
  Using size-exclusion chromatography, sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and a spectrophotometric enzyme assay, we identified the secreted gamma-glutamyl transpeptidase of H pylori (HPGGT) as the factor responsible for inhibition of T-cell proliferation.
  
  
  RESULTS
  Mutagenesis of HPGGT in different H pylori strains completely abrogated this inhibitory effect. Recombinantly expressed HPGGT protein showed full antiproliferative activity. Site-directed mutagenesis and application of the GGT inhibitor acivicin revealed that inhibition of T cells depends on catalytic activity of HPGGT. Cell cycle analysis of human T cells indicated that HPGGT was necessary and sufficient to induce G(1) arrest. Reduced levels of c-Myc and phosphorylated c-Raf protein suggest the disruption of Ras-dependent signaling by HPGGT.
  
  
  CONCLUSIONS
  GGT is a novel immunosuppressive factor of H pylori inhibiting T-cell proliferation by induction of a cell cycle arrest in the G(1) phase.
authors.affiliation: Department of Medicine II, Technical University of Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmees
authors.forename: Christian
authors.initials: C
authors.lastname: Prinz
authors.forename: Tilman
authors.initials: T
authors.lastname: Treptau
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.forename: Ludger
authors.initials: L
authors.lastname: Hengst
authors.forename: Petra
authors.initials: P
authors.lastname: Voland
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Lena
authors.initials: L
authors.lastname: Brenner
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000502:physiology; D015964:Gene Expression Regulation, Bacterial; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D007371:Interferon-gamma; D005723:gamma-Glutamyltransferase