title: Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses.
abstract: Activation of dendritic cells by ligands for Toll-like receptors (TLR) is a crucial event in the initiation of innate and adaptive immune responses. Several classes of TLR ligands have been identified that interact with distinct members of the TLR-family. TLR4 ligands include lipopolysaccharide derived from different Gram-negative bacteria and viral proteins. Recent reports have demonstrated the TLR-mediated activation of dendritic cells by heat shock proteins (HSPs). However, doubts were raised as to what extent this effect was due to lipopolysaccharide contaminations of the HSP preparations. We re-examined this phenomenon using Gp96 or its N-terminal domain, nominally endotoxin-free (<0.5 enzyme units/mg). As described previously, innate immune cells are activated by Gp96 at high concentrations (> or =50 microg/ml) but not at lower concentrations. However, preincubation of low amounts of Gp96 with TLR2 and TLR4 ligands at concentrations unable to activate dendritic cells by themselves results in the production of high levels of proinflammatory cytokines, up-regulation of activation markers, and amplification of T cell activation. Our results provide significant new insights into the mechanism of HSP-mediated dendritic cell activation and present a new function of HSPs in the amplification of dendritic cell activation by bacterial products and induction of adaptive immune responses.
authors.affiliation: Institute of Immunology, University of Mainz, Obere Zahlbacherstrasse 67, 55131 Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Warger
authors.forename: Nobert
authors.initials: N
authors.lastname: Hilf
authors.forename: Gerd
authors.initials: G
authors.lastname: Rechtsteiner
authors.forename: Philipp
authors.initials: P
authors.lastname: Haselmayer
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Carrick
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
authors.forename: Philipp
authors.initials: P
authors.lastname: von Landenberg
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Nicchitta
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004285:Dogs; D004731:Endotoxins / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051195:Toll-Like Receptor 2 / Q000737:chemistry*; D051197:Toll-Like Receptor 4 / Q000737:chemistry*
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C053387:endoplasmin