title: Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori.
abstract: OBJECTIVE
  Recognition of infection leads to induction of adaptive immunity through activation of antigen-presenting cells (APCs). Among APCs, dendritic cells (DCs) have the unique capacity to deliver antigens from the periphery to T cells in secondary lymphoid organs.
  
  
  METHODS
  We analyzed molecular mechanisms of the Helicobacter pylori-induced APC activation in vitro and investigated the influence of Myd88 signaling on the phenotype of adaptive immunity to H pylori in a murine infection model.
  
  
  RESULTS
  The adaptor protein Myd88 mediates Toll-like receptor (TLR), interleukin (IL)-1, and IL-18 signaling. DCs from wild-type, IL-1R(-/-), and IL-18(-/-) mice responded to H pylori with secretion of proinflammatory cytokines and up-regulation of major histocompatibility complex II and costimulatory molecules. In Myd88(-/-) DCs these processes were impaired profoundly, showing that TLR-dependent H pylori-sensing affects DC activation. Analysis of the H pylori-specific DC transcriptome revealed that large parts of the bacteria-induced transcriptional changes depended on Myd88 signaling, comprising numerous genes involved in crucial steps of immune regulation, such as DC maturation/differentiation, antigen uptake/presentation, and effector cell recruitment/activation. The impaired ability of Myd88(-/-) DCs, B cells, and macrophages to mount a proinflammatory response to H pylori in vitro was reflected in vivo by reduced gastric inflammation and increased bacterial colonization in Myd88-deficient mice. Furthermore, Helicobacter-specific IgG2c/IgG1 ratios were reduced in Myd88(-/-) animals, suggesting the involvement of the Myd88-dependent pathway in the instruction of adaptive immunity toward a T helper cell type 1 phenotype.
  
  
  CONCLUSIONS
  A principal pathway by which DCs sense H pylori and become activated is the TLR-dependent signaling cascade. In vivo, Myd88 signaling affects adaptive immunity to the bacterium.
authors.affiliation: 2nd Department of Internal Medicine and Gastroenterology, Technical University of Munich, Munich, Germany. roland.rad@lrz.tum.de <roland.rad@lrz.tum.de>
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.forename: Lena
authors.initials: L
authors.lastname: Brenner
authors.forename: Anne
authors.initials: A
authors.lastname: Krug
authors.forename: Petra
authors.initials: P
authors.lastname: Voland
authors.forename: Jörg
authors.initials: J
authors.lastname: Mages
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Susanne
authors.initials: S
authors.lastname: Schwendy
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Anar
authors.initials: A
authors.lastname: Dossumbekova
authors.forename: Wibke
authors.initials: W
authors.lastname: Ballhorn
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Christian
authors.initials: C
authors.lastname: Prinz
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005756:Gastritis / Q000276:immunology* / Q000382:microbiology; D020869:Gene Expression Profiling; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors