Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo

Toll-like receptors (TLRs) are able to interact with pathogen-derived products and their signals induce the coordinated activation of innate and adaptive immune mechanisms. Dendritic cells (DCs) play a central role in these events. As the different TLRs are able to trigger MyD88/TRIF-dependent and -...

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Veröffentlicht in:Blood 2006-07, Vol.108 (2), p.544-550
Hauptverfasser: Warger, Tobias, Osterloh, Philipp, Rechtsteiner, Gerd, Fassbender, Melanie, Heib, Valeska, Schmid, Beate, Schmitt, Edgar, Schild, Hansjörg, Radsak, Markus P.
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container_end_page 550
container_issue 2
container_start_page 544
container_title Blood
container_volume 108
creator Warger, Tobias
Osterloh, Philipp
Rechtsteiner, Gerd
Fassbender, Melanie
Heib, Valeska
Schmid, Beate
Schmitt, Edgar
Schild, Hansjörg
Radsak, Markus P.
description Toll-like receptors (TLRs) are able to interact with pathogen-derived products and their signals induce the coordinated activation of innate and adaptive immune mechanisms. Dendritic cells (DCs) play a central role in these events. As the different TLRs are able to trigger MyD88/TRIF-dependent and -independent signaling pathways, we wondered if the simultaneous activation of these signaling cascades would synergize with respect to DC activation and induce superior cytotoxic T-lymphocyte (CTL) activity in vivo. We observed that indeed the combined activation of MyD88-dependent and -independent signaling induced by TLR7 and TLR3 ligands provoked a more rapid and more sustained bone marrow–derived DC (BMDC) activation with regard to the secretion of proinflammatory cytokines, like IL-6 and IL-12p70, and the expression of costimulatory molecules like CD40, CD70, and CD86. Furthermore, in the presence of combined TLR ligand–stimulated DCs, CD4+ and CD8+ T cells were insensitive toward the inhibitory effects of regulatory T cells. Most importantly, peptide-loaded BMDCs stimulated by TLR ligand combinations resulted in a marked increase of CTL effector functions in wild-type mice in vivo. Thus, our results provide evidence that unlocking the full potential of DCs by advanced activation protocols will boost their immunogenic potential and improve DC-based vaccination strategies.
doi_str_mv 10.1182/blood-2005-10-4015
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subjects Adaptor Proteins, Signal Transducing - metabolism
Animals
Biological and medical sciences
Bone Marrow Cells
Dendritic Cells - immunology
Dendritic Cells - metabolism
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Immunity
Immunobiology
Ligands
Membrane Glycoproteins - immunology
Membrane Glycoproteins - metabolism
Mice
Mice, Inbred C57BL
Modulation of the immune response (stimulation, suppression)
Myeloid Differentiation Factor 88
Signal Transduction
T-Lymphocytes
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Regulatory
Toll-Like Receptor 3 - immunology
Toll-Like Receptor 3 - metabolism
Toll-Like Receptor 7 - immunology
Toll-Like Receptor 7 - metabolism
Toll-Like Receptors - immunology
Toll-Like Receptors - metabolism
title Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo
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