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

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.

Keywords: Dendritic Cells, H pylori, Tregs, IL-17

Abbreviations used in this paper: AL-DC, dendritic cells pulsed with Acinetobacter lwoffii, DC, dendritic cell, EC-DC, dendritic cells pulsed with Escherichia coli, FACS, fluorescence-activated cell sorting, HP-DC, dendritic cells pulsed with Helicobacter pylori, IFN-γ, interferon γ, IL-10, interleukin-10, PBS-DC, dendritic cells pulsed with phosphate-buffered saline, PCR, polymerase chain reaction, TGF-β, transforming growth factor β, Th17 cells, interleukin-17⁺ helper T, Treg, regulatory T cell