title: A secreted low-molecular-weight protein from Helicobacter pylori induces cell-cycle arrest of T cells.
abstract: OBJECTIVE
  Although Helicobacter pylori is recognized by the human immune system, the bacteria are not eliminated and lead to a chronic inflammation of the gastric mucosa.
  
  
  METHODS
  We investigated the interaction of H. pylori with human lymphocytes. T and B lymphocytes were isolated from H. pylori-infected patients and stimulated with anti-CD3/CD28 or interleukin-6.
  
  
  RESULTS
  Proliferation of lymphocytes was abolished on co-incubation with different H. pylori strains (1-5 bacteria/cell) or with protein extracts of culture supernatants. Inhibition of proliferation was independent of known virulence factors. The factor is a protein or protein complex with an apparent molecular weight between 30 and 60 kilodaltons, clearly distinct from VacA. Although antigen-specific activation of T cells (as shown by nuclear factor of activated T cells [NFAT]-activation, interferon-gamma production, and CD25 or CD69 up-regulation) remained intact, cell-cycle analysis showed that S-phase entry of T cells was inhibited completely by H. pylori. Consequently, stimulated T cells arrested in the G1 phase of the cell cycle. Western blot analysis showed markedly reduced phosphorylation of the retinoblastoma protein (pRb), suggesting inhibition of G1 cyclin-dependent kinase activity. In line with this, activities of cyclin D3 and cyclin E were down-regulated, and levels of the cyclin-dependent kinase inhibitor p27Kip1 were increased. Mouse embryonic fibroblasts deficient in p27 showed a decrease in H. pylori-induced inhibition of cell proliferation, suggesting a central role for p27 in mediating H. pylori-induced G1 arrest.
  
  
  CONCLUSIONS
  Induction of cell-cycle arrest in lymphocytes may be of major significance for the chronic persistence of bacteria in the human stomach.
authors.affiliation: Department of Medicine II, Technical University, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
authors.forename: Christian
authors.initials: C
authors.lastname: Schmees
authors.forename: Petra
authors.initials: P
authors.lastname: Voland
authors.forename: Nicole
authors.initials: N
authors.lastname: Endres
authors.forename: Markus
authors.initials: M
authors.lastname: Sander
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.forename: Madlene
authors.initials: M
authors.lastname: Oelsner
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Martin
authors.initials: M
authors.lastname: Mempel
authors.forename: Ludger
authors.initials: L
authors.lastname: Hengst
authors.forename: Christian
authors.initials: C
authors.lastname: Prinz
mesh_terms: D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D019925:Cyclin A / Q000378:metabolism; D056743:Cyclin D3; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000276:immunology*; D006133:Growth Substances / Q000378:metabolism; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology; D008970:Molecular Weight; D015398:Signal Transduction / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D001426:Bacterial Proteins; C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D006133:Growth Substances; D025521:Tumor Suppressor Proteins; C074689:VacA protein, Helicobacter pylori; D050760:Cyclin-Dependent Kinase Inhibitor p27