title: Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice.
abstract: OBJECTIVE
  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-beta (TGF-beta), 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-beta 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.
authors.affiliation: 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, USA. jykao@umich.edu
authors.forename: John Y
authors.initials: JY
authors.lastname: Kao
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Jason C
authors.initials: JC
authors.lastname: Mills
authors.forename: Baomei
authors.initials: B
authors.lastname: Wang
authors.forename: Maochang
authors.initials: M
authors.lastname: Liu
authors.forename: Kathyn A
authors.initials: KA
authors.lastname: Eaton
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.forename: Bradford E
authors.initials: BE
authors.lastname: Berndt
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Cole
authors.forename: Tomomi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Stephanie Y
authors.initials: SY
authors.lastname: Owyang
authors.forename: Jay
authors.initials: J
authors.lastname: Luther
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005753:Gastric Mucosa / Q000276:immunology* / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000254:growth & development / Q000276:immunology*; D057131:Immune Evasion; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D036641:Microscopy, Fluorescence, Multiphoton; D012333:RNA, Messenger / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; D016753:Interleukin-10