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

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

doi:10.1053/j.gastro.2007.02.031

Cited by 164 publications

(168 citation statements)

References 46 publications

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“…H. pylori is known to strongly affect the cell cycle of infected cells: G 1 /S and also G 2 /M cell cycle delays have been reported. [14][15][16][17][18] In our study, several observations point towards a strong contribution of an H. pylori-induced G 2 /M delay.…”

Section: H Pylorisupporting

confidence: 60%

“…These findings are in accordance with other studies reporting H. pylori-induced G 1 /S and G 2 /M cell cycle delays. [14][15][16][17][18] Since the pH3Ser10 status is cell cycle-dependent, a new set of experiments was carried out using stricter cell cycle synchronization conditions, such as low serum starvation for 48 h and subsequent release with 10% FCS. In non-infected AGS cells, pH3Ser10 levels gradually increased with time (Suppl.…”

Section: H Pylorimentioning

confidence: 99%

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Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

Fehri¹,

Rechner²,

Janßen³

et al. 2009

Epigenetics

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Section: H Pylorisupporting

confidence: 60%

Section: H Pylorimentioning

confidence: 99%

Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

Fehri¹,

Rechner²,

Janßen³

et al. 2009

Epigenetics

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“…Here, we extend these findings and implicate two H. pylori virulence determinants, VacA and GGT, in DC tolerization. Both factors were previously known to share several important properties: They both facilitate murine colonization (16,17), inhibit human T-cell activation (18)(19)(20)25), and induce epithelial cell apoptosis (26,27). The evidence now provided here documents a unique role for VacA and GGT in DC tolerization and links the tolerizing effects of both factors on DCs to persistence: (i) The H. pylori-induced inhibition of DC maturation depends on the (nonredundant) activity of both factors; (ii) the induction of Treg properties in naive T cells by H. pylori-experienced DCs likewise depends on both factors, and strains lacking either VacA or GGT due to targeted gene deletion (iii) fail to colonize mice at wild-type levels, and, in the case of the ΔvacA mutant (iv) induce somewhat stronger Th1 and Th17 responses and gastric pathology and fail to protect against allergen-induced asthma.…”

Section: Discussionmentioning

confidence: 99%

“…pylori Strains and Culture Conditions. The following previously published or newly generated strains of H. pylori were used: PMSS1 (9), PMSS1ΔvacA (generated by consecutive natural transformation of G27ΔvacA gDNA into H. pylori strain SS1, and of SS1ΔvacA gDNA into H. pylori strain PMSS1), PMSS1Δggt (generated by natural transformation of G27Δggt gDNA) (20), G27 (37), G27ΔvacA (deficient for the entire vacuolating cytotoxin gene; generously provided by H. Kusters, Department of Microbiology, University of Utrecht Medical Center, Utrecht, The Netherlands), P12, P12Δggt, P12ΔvacA, and P12Δggt/ ΔvacA (obtained by replacing a P12ΔvacA mutant's entire ggt gene by a kanamycin resistance cassette and subsequent selection on chloramphenicol and kanamycin plates). All P12 strains are described in ref.…”

Section: Methodsmentioning

confidence: 99%

“…The immunomodulatory activity of both factors has been attributed to suppressive effects on human T cells (18)(19)(20); murine T cells, in contrast, are known to be resistant to VacA (21). To examine whether the tolerogenic effects of H. pylori on DCs in vivo are dependent on T cells, we infected mice lacking α/β T cells due to a targeted deletion of the T-cell receptor (TCR) β-chain with wild-type and mutant H. pylori PMSS1 as neonates and/ or as adults.…”

Section: Dc-mediated Neonatally Acquired Immune Tolerance To H Pylorimentioning

confidence: 99%

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Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

Oertli

Noben

Engler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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208

190

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Infection with the gastric bacterial pathogen Helicobacter pylori is typically contracted in early childhood and often persists for decades. The immunomodulatory properties of H. pylori that allow it to colonize humans persistently are believed to also account for H. pylori's protective effects against allergic and chronic inflammatory diseases. H. pylori infection efficiently reprograms dendritic cells (DCs) toward a tolerogenic phenotype and induces regulatory T cells (Tregs) with highly suppressive activity in models of allergen-induced asthma. We show here that two H. pylori virulence determinants, the γ-glutamyl transpeptidase GGT and the vacuolating cytotoxin VacA, contribute critically and nonredundantly to H. pylori's tolerizing effects on murine DCs in vitro and in vivo. The tolerancepromoting effects of both factors are independent of their described suppressive activity on T cells. Isogenic H. pylori mutants lacking either GGT or VacA are incapable of preventing LPS-induced DC maturation and fail to drive DC tolerization as assessed by induction of Treg properties in cocultured naive T cells. The Δggt and ΔvacA mutants colonize mice at significantly reduced levels, induce stronger T-helper 1 (Th1) and T-helper 17 (Th17) responses, and/or trigger more severe gastric pathology. Both factors promote the efficient induction of Tregs in vivo, and VacA is required to prevent allergen-induced asthma. The defects of the Δggt mutant in vitro and in vivo are phenocopied by pharmacological inhibition of the transpeptidase activity of GGT in all readouts. In conclusion, our results reveal the molecular players and mechanistic basis for H. pyloriinduced immunomodulation, promoting persistent infection and conferring protection against allergic asthma.bacterial virulence factors | hygiene hypothesis | persistent bacterial infection | human microbiota | persistence strategies T he bacterial pathogen Helicobacter pylori persistently colonizes the gastric mucosa of humans. It is typically acquired in early childhood (1) and, in the absence of antibiotic therapy, may persist for the entire lifespan of the host (2, 3). The extraordinary ability of H. pylori to resist a vigorous adaptive immune response driven in large part by T-helper 1 (Th1) and/or T-helper 17 (Th17)-polarized effector T cells (4, 5) has been attributed to its perfect adaptation to-and manipulation of-the human innate and adaptive immune systems (6). H. pylori has colonized its human host for at least 60,000 y (7) and during this long period of coevolution has evolved elaborate ways to systemically manipulate adaptive immune responses and to promote its persistence through the preferential induction of regulatory T-cell (Treg) over T-effector cell responses. Treg-predominant responses are characteristic of heavily colonized but asymptomatic carriers (4) and of children with particularly mild forms of Helicobacter-associated gastritis (8). Several recent functional studies using experimentally infected animals have implicated Tregs and dendritic cells (...

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CampylobacterandHelicobacter

Joens¹

2004

Pathogenesis of Bacterial Infections in Animals

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

Cited by 164 publications

References 46 publications

Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

CampylobacterandHelicobacter

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