Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

Abstract

Dendritic cell activation by Toll-like receptors (TLR) is crucial for the generation of protective immune responses. In addition to the common myeloid differentiation factor 88 (MyD88)-dependent signaling pathway, TLR4 engages the adaptor protein Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-g (TRIF), leading to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. Using microarray expression profiling we now identify TRIF as a major regulator of the TLR4-triggered activation program of dendritic cells. We show that the expression of 47% of the genes that are responsive to TLR4 stimulation in wild-type dendritic cells is significantly altered in cells carrying a loss-of-function mutation of TRIF. Specifically, expression of IL-12, IL-18, and IL-23 was impaired in the absence of functional TRIF, suggesting that TLR4-promoted Th1 responses are TRIFdependent. Furthermore, we provide evidence that TRIF regulates TLR4-mediated gene expression both by type I IFN-dependent and -independent mechanisms. Whereas dendritic cell production of CXCL10 and CCL12 was dependent on both TRIF and the type I interferon receptor, expression of IL-6 required TRIF but not type I interferon activity. Functional TRIF was also required for the normal induction of numerous genes considered important for host defense against diverse pathogens. Together, these data therefore identify TRIF as a crucial regulator of TLR4-dependent dendritic cell responses.

Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

“…An early study identified Peli1 as one of the TRIF-dependent genes induced by the TLR4 ligand LPS in dendritic cells. 67 This finding has been confirmed and extended by a recent work demonstrating that Peli1 is induced at both RNA and protein levels in response to stimulation by both LPS and the TLR3 ligand polyIC. 12 These TRIF-dependent TLRs are known to activate the IKK-related kinases, TBK1 and IKKe, which in turn induce the nuclear translocation of the transcription factor IFN-regulatory factor 3 (IRF3) and induction of type I IFNs.…”

Lipopolysaccharide and Double-stranded RNA Up-regulate Toll-like Receptor 2 Independently of Myeloid Differentiation Factor 88

“…These observations indicate that mechanisms leading to regulation of CD80/86, TLR4, and TLR2 differ. TRIF is suggested as a main adapter molecule leading LPS/lipid A up-regulation of CD80/86 and TLR3 (54,69). We hypothesize that TRIF also plays an important role in LPS-and poly(I-C)-induced regulation of TLR2 and other TLRs.…”

The human adaptor SARM negatively regulates adaptor protein TRIF–dependent Toll-like receptor signaling

“…For example, TRIF is important in resistance to cytomegalovirus infection 10 , in the LPS-induced upregulation of costimulatory molecules on antigen-presenting cells 29 and in mediating the TLR4-induced cell activation program in dendritic cells 30 . The importance of TRIF in the antiviral response is emphasized by the fact that it is targeted for immune evasion by the vaccinia virus protein A46R 27 and also by the hepatitis C virus protease NS3-4A 31 .…”