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 -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.
Warger
Tobias
T
Institute for Immunology, Johannes Gutenberg University, Mainz, Germany.
Osterloh
Philipp
P
Rechtsteiner
Gerd
G
Fassbender
Melanie
M
Heib
Valeska
V
Schmid
Beate
B
Schmitt
Edgar
E
Schild
Hansjörg
H
Radsak
Markus P
MP
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007109:Immunity; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D015398:Signal Transduction; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D008024:Ligands; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors