Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice.
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.
Kao
John Y
JY
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
Zhang
Min
M
Miller
Mark J
MJ
Mills
Jason C
JC
Wang
Baomei
B
Liu
Maochang
M
Eaton
Kathyn A
KA
Zou
Weiping
W
Berndt
Bradford E
BE
Cole
Tyler S
TS
Takeuchi
Tomomi
T
Owyang
Stephanie Y
SY
Luther
Jay
J
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
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