<i>Helicobacter pylori</i>Stimulates Dendritic Cells To Induce Interleukin-17 Expression from CD4<sup>+</sup>T Lymphocytes

Khamri, Wafa; Walker, Marjorie M.; Clark, P.; Atherton, John C.; Thursz, Mark; Bamford, Kathleen B.; Lechler, Robert I.; Lombardi, Giovanna

doi:10.1128/iai.00524-09

Cited by 84 publications

(87 citation statements)

References 64 publications

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“…This observation is in agreement with previous reports describing reduced IL-12 secretion by H. pylori-primed DCs (29,36,37) and the involvement of CagA in the suppression of IL-12p40 expression (31); however, the possible signaling pathways implicated remain unclear. We speculate that activation of STAT3 might be also involved in preventing IL-12 release, because STAT3 was found to negatively regulate the IL-12p40 promoter (38), whereas in tumor-associated DCs, STAT3 inhibits NF-ĸB/c-Rel-dependent IL-12p35 expression (39).…”

Section: Discussionsupporting

confidence: 93%

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

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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.

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Section: Discussionsupporting

confidence: 93%

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

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“…13 H. pylori-pulsed DCs (HP-DC) promote a type 1 helper T cell (Th1) response [14][15][16][17][18][19][20] and, as shown more recently, an interleukin (IL)-17-producing helper T cell (Th17) response. 21 Several studies have suggested the immunoregulatory effects of H. pylori on DCs. We showed that H. pylori-secreted factors inhibit DC IL-12 production.…”

Section: Helicobacter Pylori Directs Tolerogenic Programming Of Dendrmentioning

confidence: 99%

Helicobacter pyloridirects tolerogenic programming of dendritic cells

et al. 2010

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3 Gastric CD103 + dendritic cells, which are known to induce mucosal regulatory T cells, were also increased in number, raising the question whether H. pylori infection induces a regulatory T cell-skewed response by way of a bacteria-dendritic cell interaction. In fact, bone marrow-derived dendritic cells underwent tolerogenic programming, skewing the balance between effector and regulatory T cell responses towards regulatory T cell differentiation in a transforming growth factor-β-and interleukin-10-dependent manner. Depletion of regulatory T cell numbers augmented H. pylorispecific effector helper T cell responses, which correlated with a lower degree of H. pylori colonization. These results suggest H. pylori is capable of inducing a regulatory T cell-skewed response that limits the host's ability to eradicate the bacteria, allowing the H. pylori infection to persist. To better understand the mechanism of H. pylori tolerogenic programming we compared the differential expressions of 34 genes critical for dendritic cell function in bone marrowderived dendritic cells pulsed with live H. pylori or other Gram-negative bacteria (e.g., Escherichia coli, Acinetobacter lwoffii). Our data imply that H. pylori targets the Toll-like receptor 2 pathway to induce a regulatory T cell-skewed response. In addition, we show that H.

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“…Furthermore, DCs may also interact with H. pylori through CD209 (DC-SIGN) that binds H. pylori lipopolysaccharide (LPS) and promotes IL-10 secretion (13). Moreover, H. pylori stimulates DCs to induce IL-17 expression in CD4 ϩ lymphocytes (45). Since myeloid APCs are found in the gastric mucosa and are involved in H. pylori-specific immune responses and are, therefore, potential targets of bacterial virulence factors promoting immune evasion, we were interested in elucidating the immunomodulating effects of H. pylori on human APCs.…”

mentioning

confidence: 99%

Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes

et al. 2012

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Helicobacter pyloriStimulates Dendritic Cells To Induce Interleukin-17 Expression from CD4⁺T Lymphocytes

Cited by 84 publications

References 64 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 pyloridirects tolerogenic programming of dendritic cells

Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes

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Helicobacter pyloriStimulates Dendritic Cells To Induce Interleukin-17 Expression from CD4+T Lymphocytes

Cited by 84 publications

References 64 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 pyloridirects tolerogenic programming of dendritic cells

Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes

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Helicobacter pyloriStimulates Dendritic Cells To Induce Interleukin-17 Expression from CD4⁺T Lymphocytes