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Blood, 15 July 2006, Vol. 108, No. 2, pp. 544-550.
Prepublished online as a Blood First Edition Paper on March 14, 2006; DOI 10.1182/blood-2005-10-4015.
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IMMUNOBIOLOGY
Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo
Tobias Warger,
Philipp Osterloh,
Gerd Rechtsteiner,
Melanie Fassbender,
Valeska Heib,
Beate Schmid,
Edgar Schmitt,
Hansjörg Schild, and
Markus P. Radsak
From the Institute for Immunology, Johannes Gutenberg University; and the Third Department of Medicine, Johannes Gutenberg University Hospital, Mainz, Germany.
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.
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