Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation.
Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, a process involving up-regulation of MHC and costimulatory molecules and secretion of proinflammatory cytokines. All TLRs except TLR3 achieve these outcomes by using the signaling adaptor myeloid differentiation factor 88. TLR4 and TLR3 can both use the Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN-β and -α4. The TRIF signaling pathway, downstream of both of these TLRs, also leads to DC maturation, and it has been proposed that the type I IFNs act in cis to induce DC maturation and subsequent effects on adaptive immunity. The present study was designed to understand the molecular mechanisms of TRIF-mediated DC maturation. We have discovered that TLR4-TRIF-induced DC maturation was independent of both IRF3 and type I IFNs. In contrast, TLR3-mediated DC maturation was completely dependent on type I IFN feedback. We found that differential activation of mitogen-activated protein kinases by the TLR4- and TLR3-TRIF axes determined the type I IFN dependency for DC maturation. In addition, we found that the adjuvanticity of LPS to induce T-cell activation is completely independent of type I IFNs. The important distinction between the TRIF-mediated signaling pathways of TLR4 and TLR3 discovered here could have a major impact in the design of future adjuvants that target this pathway.
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093.
Wei
W
Hu
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093.
Aakanksha
A
Jain
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093.
Yajing
Y
Gao
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093.
Igor M
IM
Dozmorov
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093.
Rajakumar
R
Mandraju
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093.
Edward K
EK
Wakeland
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093 chandrashekhar.pasare@utsouthwestern.edu.
Chandrashekhar
C
Pasare
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D008070:Lipopolysaccharides; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse
LPS | Poly I:C | MAVS; MAP kinases; NF-κB activation