title: CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection.
abstract: Gastric epithelial cells (GECs) are the primary target for Helicobacter pylori infection and may act as APCs regulating local T cell responses. We previously reported that H. pylori infection of GECs induces the expression of the T cell coinhibitory molecule B7-H1 on GECs. This process contributes to the hyporesponsiveness of CD4(+) effector T cells and accumulation of regulatory T cells. In the present study, we investigated the impact of H. pylori cytotoxin-associated gene A (CagA) on the modulation of the expression of the T cell costimulator B7-H2 by GECs. B7-H2 is involved in promoting Th17 type responses. H. pylori infection downregulates B7-H2 expression by GECs in a CagA-dependent manner. IFN-γ, which is increased in the H. pylori-infected gastric mucosa, synergizes with H. pylori in downregulating B7-H2 expression by GECs. CagA-mediated modulation of B7-H2 on GECs involves p70 S6 kinase phosphorylation. The CagA-dependent B7-H2 downregulation in GECs correlates with a decrease in Th17 type responses in vitro and in vivo. Furthermore, CagA-dependent modulation of Th17 responses was inversely correlated with the H. pylori colonization levels in vivo. Our data suggest that CagA contributes to the ability of H. pylori to evade Th17-mediated clearance by modulating expression of B7-H2 and, thus, to the establishment of the H. pylori chronic infection.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Taslima T
authors.initials: TT
authors.lastname: Lina
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pinchuk
authors.forename: Jennifer
authors.initials: J
authors.lastname: House
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
authors.forename: David Y
authors.initials: DY
authors.lastname: Graham
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Beswick
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reyes
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D005753:Gastric Mucosa / Q000276:immunology* / Q000382:microbiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D060945:Inducible T-Cell Co-Stimulator Ligand; C080866:cagA protein, Helicobacter pylori; D007371:Interferon-gamma; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases