Release of IL-12 by dendritic cells activated by TLR ligation is dependent on MyD88 signaling, whereas TRIF signaling is indispensable for TLR synergy.
Recently, it has been shown that certain combinations of TLR ligands act in synergy to induce the release of IL-12 by DCs. In this study, we sought to define the critical parameters underlying TLR synergy. Our data show that TLR ligands act synergistically if MyD88- and TRIF-dependent ligands are combined. TLR4 uses both of these adaptor molecules, thus activation via TLR4 proved to be a synergistic event on its own. TLR synergy did not affect all aspects of DC activation but enhanced primarily the release of certain cytokines, particularly IL-12, whereas the expression of costimulatory molecules remained unchanged. Consequently, synergistic activation of DC did not affect their ability to induce T cell proliferation but resulted in T(H)1-biased responses in vitro and in vivo. Furthermore, we examined the impact of TLR ligand combinations on primary DC in vitro but observed only modest effects with a combination of CpG + Poly (I:C). However, noticeable synergy in terms of IL-12 production by DCs was detectable in vivo after systemic administration of CpG + Poly (I:C). Finally, we show that synergy is partially dependent on IFNAR signaling but does not require the release of IFNs to the enviroment, suggesting an autocrine action of type I IFNs.
Krummen
Mathias
M
Department of Dermatology, University of Mainz, Mainz, Germany. krummen@hautklinik.klinik.uni-mainz.de
Balkow
Sandra
S
Shen
Limei
L
Heinz
Stefanie
S
Loquai
Carmen
C
Probst
Hans-Christian
HC
Grabbe
Stephan
S
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology; D016764:Cell Polarity; D003713:Dendritic Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D019013:CD40 Antigens; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011070:Poly I-C; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse