Helicobacter pylori Immune Escape Is Mediated by Dendritic Cell–Induced Treg Skewing and Th17 Suppression in Mice
Received 13 February 2009; accepted 12 November 2009. published online 19 November 2009. Uncorrected Proof
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.
⁎Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan
‡Department of Pathology and Immunology, Washington University, St Louis, Missouri
§Department of Microbiology and Immunology, University of Michigan Health System, Ann Arbor, Michigan
∥Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan
Reprint requests Address requests for reprints to: John Y. Kao, MD, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Health System, 6520A MSRB I, SPC 5682, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5682. fax: (734) 763-2535
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.
Author contributions were as follows: J.Y.K. provided study concept and design, acquired data; analyzed and interpreted data, drafted the manuscript, critically revised the manuscript for important intellectual content; analyzed statistics, obtained funding; provided technical or material support, and supervised the study. M.Z. provided study concept and design, acquired data, analyzed and interpreted data, analyzed statistics, provided technical or material support, and supervised the study. M.J.M. and J.C.M. acquired data, analyzed and interpreted data, critically revised the manuscript for important intellectual content, and provided technical and material support. B.W. and M.L. acquired data, analyzed and interpreted data, and provided technical support. K.A.E. analyzed and interpreted data, critically revised the manuscript for important intellectual content, and provided technical and material support. W.Z. critically revised the manuscript for important intellectual content and provided technical and material support. B.E.B. acquired data, analyzed and interpreted data, and provided technical support. T.S.C., T.T., and S.Y.O. acquired data and analyzed and interpreted data. J.L. acquired data, analyzed and interpreted data, and critically revised the manuscript for important intellectual content.
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