Dendritic Cells Prevent Rather Than Promote Immunity Conferred by a Helicobacter Vaccine Using a Mycobacterial Adjuvant

Hitzler, Iris; Oertli, Mathias; Becher, Burkhard; Agger, Else Marie; Müller, Anne

doi:10.1053/j.gastro.2011.04.009

Cited by 60 publications

(64 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous reports showed that DCs exposed to H. pylori fail to induce an effector T cell response of the Th17 type in vitro and in vivo (10,40,41). In line with these observations, we did not detect enhanced secretion of IL-17A from CD4 + T cells cocultured with H. pylori-primed DCs.…”

Section: Discussionsupporting

confidence: 90%

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

Kaebisch

Mejías-Luque

Prinz

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Helicobacter pylori infection induces chronic gastric inflammation that can progress to cancer. In this process, the virulence factor cytotoxin-associated gene A (CagA) plays a central role by directly altering epithelial cell signaling and inducing a strong Th1 immune response, which contributes to carcinogenesis. It is still barely understood how the bacterium evades clearance despite this solid immune response and persists lifelong. Dendritic cells (DCs) play a major role in determining the adaptive immune response toward H. pylori, and high levels of regulatory T cells have been detected infiltrating the gastric mucosa of H. pylori–infected patients, which contribute to bacterial persistence. Although murine studies indicate that H. pylori induces tolerization of DCs and impairs DC maturation, the virulence determinants involved are still controversial. Moreover, the signaling cascades engaged in human DC tolerization upon H. pylori infection remain unknown. In the current study, we analyzed the effect of H. pylori infection on human DC maturation and function, focusing on the virulence factors implicated and signaling pathways involved. Our results reveal that CagA is crucial for DC tolerization by modulating IL-10 secretion and, in turn, STAT3 phosphorylation, favoring a regulatory T cell immune response. Our findings help to unravel the paradox why CagA-positive strains, although eliciting a stronger inflammatory response, have overcome evolutionary pressure and persisted in their human host.

show abstract

Section: Discussionsupporting

confidence: 90%

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

Kaebisch

Mejías-Luque

Prinz

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Several recent functional studies using experimentally infected animals have implicated Tregs and dendritic cells (DCs) with "tolerogenic" activity in mediating the local and systemic immunomodulatory effects of H. pylori infection (9-12). The depletion of Tregs in a genetic model resulted in spontaneous clearance of the infection (9) and greatly improved the efficacy of an H. pylori vaccine (10). H. pylori-induced Tregs differentiate in the periphery as a result of their priming by tolerogenic DCs (13), which convert naive T cells into FoxP3 + Tregs through antigen presentation in the absence of costimulatory signals or cytokines (13,14).…”

mentioning

confidence: 99%

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.

Self Cite

208

190

View full text Add to dashboard Cite

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 (...

show abstract

“…We and others (16)(17)(18)(19) have shown that the spontaneous as well as the vaccine-induced control of Helicobacter infection depends on MHC class II-restricted, Th1-and Th17-polarized T cells. Speculating that the T cell-intrinsic expression of miR-155 is required to activate T cells and to generate IFN-g-and/or IL-17-producing effector cells, we treated immunomagnetically purified CD4 + CD25 2 T cells with anti-CD3/anti-CD28 in vitro.…”

Section: Mir-155 2/2 T Cells Proliferate Less and Produce Less Ifn-g mentioning

confidence: 99%

“…pylori-specific vaccination and challenge wt mice that receive three doses of an orally administered wholecell H. pylori vaccine adjuvanted with cholera toxin develop protective immunity against challenge infection with the pathogen (16,18). To assess whether miR-155 2/2 mice are protected as well as wt mice, groups of both genotypes were vaccinated three times at weekly intervals prior to autologous challenge infection with the commonly used H. pylori vaccine strain SS1.…”

Section: Mir-155mentioning

confidence: 99%

“…Persistent H. pylori colonization of its preferred niche, the human gastric mucosa, results in chronic gastritis (12) and predisposes carriers to a high risk of developing gastric and duodenal ulcers, gastric cancer, and gastric MALT lymphoma (13)(14)(15). We and others (16)(17)(18)(19) have reported earlier that the control of H. pylori infection in both experimental infection and vaccination/challenge models requires the activity of Th1 and *Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland; and Th17 cells. Helicobacter-specific Th1 cells and their signature cytokine IFN-g were further shown to be directly responsible for the induction of infection-associated preneoplastic pathology manifesting as chronic atrophic gastritis, epithelial hyperplasia, and intestinal metaplasia (18,20 …”

mentioning

confidence: 90%

See 1 more Smart Citation

MicroRNA-155 Is Essential for the T Cell-Mediated Control of Helicobacter pylori Infection and for the Induction of Chronic Gastritis and Colitis

Oertli

Engler

Kohler

et al. 2011

The Journal of Immunology

Self Cite

148

123

View full text Add to dashboard Cite

MicroRNAs govern immune responses to infectious agents, allergens, and autoantigens and function by posttranscriptional repression of their target genes. In this paper, we have addressed the role of microRNA-155 (miR-155) in the control of Helicobacter pylori infection of the gastrointestinal tract and the development of H. pylori-induced chronic gastritis and associated gastric preneoplastic pathology. We show that miR-155 is upregulated in the gastric mucosa of experimentally infected mice and that miR-155−/− mice fail to control H. pylori infection as a result of impaired pathogen-specific Th1 and Th17 responses. miR-155−/− mice are also less well protected against challenge infection after H. pylori-specific vaccination than their wild-type (wt) counterparts. As a consequence of their impaired T cell responses to H. pylori, miR-155−/− mice develop less severe infection-induced immunopathology manifesting as chronic atrophic gastritis, epithelial hyperplasia, and intestinal metaplasia. T cells from miR-155−/− mice that are activated by CD3/CD28 cross-linking expand less and produce less IFN-γ and IL-17 than wt T cells. Finally, we show in this paper using adoptive transfers that the phenotypes of miR-155−/− mice are likely due to T cell-intrinsic defects. In contrast to wt T cells, miR-155−/− T cells from infected donors do not control H. pylori infections in T cell-deficient recipients, do not differentiate into Th1 or Th17 cells, and do not cause immunopathology. In addition, naive miR-155−/− T cells fail to induce chronic Th17-driven colitis in an adoptive transfer model. In conclusion, miR-155 expression is required for the Th17/Th1 differentiation that underlies immunity to H. pylori infection on the one hand and infection-associated immunopathology on the other.

show abstract

Dendritic Cells Prevent Rather Than Promote Immunity Conferred by a Helicobacter Vaccine Using a Mycobacterial Adjuvant

Cited by 60 publications

References 39 publications

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

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

MicroRNA-155 Is Essential for the T Cell-Mediated Control of Helicobacter pylori Infection and for the Induction of Chronic Gastritis and Colitis

Contact Info

Product

Resources

About