Gastroenterology

Gastroenterology

Volume 138, Issue 3, March 2010, Pages 1046-1054
Gastroenterology

Basic Alimentary Tract
Helicobacter pylori Immune Escape Is Mediated by Dendritic Cell–Induced Treg Skewing and Th17 Suppression in Mice

https://doi.org/10.1053/j.gastro.2009.11.043Get rights and content

Background & Aims

Helicobacter pylori infection increases gastric regulatory T cell (Treg) response, which may contribute to H pylori immune escape. We hypothesize that H pylori directs Treg skewing by way of dendritic cells (DCs) and thus inhibits interleukin-17+ helper T cells (Th17) immunity.

Methods

Two-photon microscopy was used to locate DCs in gastric lamina propria of mice. The induction of Th17 and Treg responses by bacteria-pulsed murine bone marrow–derived DCs was analyzed by cytokine production and stimulation of T-cell proliferation. The effect of VacA, CagA, transforming growth factor-β (TGF-β), and IL-10 on Th17/Treg balance was assessed. The in vivo significance of Tregs on the H pylori–specific Th17 response and H pylori density was determined by using anti-CD25 neutralizing antibodies to deplete Tregs in mice.

Results

We showed that mucosal CD11c+ DCs are located near the surface of normal gastric epithelium, and their number increased after H pylori infection. Study of the direct interaction of DCs with H pylori showed a Treg-skewed response. The Treg skewing was independent of H pylori VacA and CagA and dependent on TGF-β and IL-10. In vivo Treg skewing by adoptive transfer of H pylori–pulsed DCs reduces the ratio of gastric IL-17/Foxp3 mRNA expressions. The depletion of CD25+ Tregs results in early reduction of H pylori density, which is correlated with enhanced peripheral H pylori–specific Th17, but not Th1, response.

Conclusions

Overall, our study indicates that H pylori alters the DC-polarized Th17/Treg balance toward a Treg-biased response, which suppresses the effective induction of H pylori–specific Th17 immunity.

Section snippets

Two-Photon Microscopy

CD11c-YFP mice were injected intravenously with 655 nm Q-dot nanocrystals (20 μL diluted in to phosphate-buffered saline [PBS] to 200 μL total volume; Invitrogen, Carlsbad, CA). Stomachs were removed and glued to plastic cover slips with VetBond, placed in Dulbecco's modified Eagle's medium, and imaged at room temperature with the use of a custom-built 2-photon microscope.18 Each sample was excited at 890 nm. Fluorescence emission was separated into blue, green, and red signals with the use of

DCs Are Found Near the Surface of the Gastric Mucosa

DCs play a key role in mediating adaptive immunity against pathogens by priming antigen-specific helper T-cell responses. Rescigno et al19 showed that DCs traverse the epithelial tight junction and sample luminal bacteria in the intestine. The presence of DCs near the gastric mucosal surface would suggest similar bacteria sampling in the gastric lumen. Two-photon microscopy20 showed the presence of many CD11c+ DCs near the luminal surface of the normal stomach of transgenic pCD11c-YFP mice21, 22

Discussion

Growing evidence suggests that H pylori–infected persons have a higher Treg response than noninfected persons; a characteristic that may contribute to immune evasion. Our observation of DCs near the surface epithelium of the gastric mucosa and their recruitment during H pylori infection is consistent with the hypothesis that DCs are critical immune mediators in the host response to H pylori infection. HP-DCs induced a lower Th17/Treg response compared with EC-DCs and AL-DCs. Deletion of VacA

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    Conflicts of interest The authors disclose no conflicts.

    Funding This study was supported by grants from the National Institutes of Health (1 KO8 DK0669907-01 to J.Y.K. and R01 DK079798-01 to J.C.M.) and the Foundation of Digestive Health and Nutrition.

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