Inhibition of T-Cell Proliferation by Helicobacter pylori γ-Glutamyl Transpeptidase

Christian Schmees, Christian Prinz, Tilman Treptau, Roland Rad, Ludger Hengst, Petra Voland, Stefan Bauer, Lena Brenner, Roland M. Schmid, Markus Gerhard

Research output: Contribution to journalArticlepeer-review

160 Scopus citations

Abstract

Background & Aims: 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 γ-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 G1 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 G1 phase.

Original languageEnglish
Pages (from-to)1820-1833
Number of pages14
JournalGastroenterology
Volume132
Issue number5
DOIs
StatePublished - May 2007

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