Collaboration of Toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses

Abstract

Dendritic cells (DCs) represent a functionally diverse and flexible population of rare cells with the unique capability of binding, internalizing and detecting various microorganisms and their components. However, the response of DCs to innocuous or pathogenic microbes is highly dependent on the type of microbe-associated molecular patterns (MAMPs) recognized by pattern recognition receptors (PRRs) that interact with phylogenetically conserved and functionally indispensable microbial targets that involve both self and foreign structures such as lipids, carbohydrates, proteins, and nucleic acids. Recently, special attention has been drawn to nucleic acid receptors that are able to evoke robust innate immune responses mediated by type I interferons and inflammatory cytokine production against intracellular pathogens. Both conventional and plasmacytoid dendritic cells (cDCs and pDCs) express specific nucleic acid recognizing receptors, such as members of the membrane Toll-like receptor (TLR) and the cytosolic RIG-I-like receptor (RLR) families. TLR3, TLR7/TLR8 and TLR9 are localized in the endosomal membrane and are specialized for the recognition of viral double-stranded RNA, single-stranded RNA, and nonmethylated DNA, respectively whereas RLRs (RIG-I, MDA5, and LGP2) are cytosolic proteins that sense various viral RNA species. In this review we discuss the significance of detecting the genomic content of viruses by DC subsets capable of linking innate and adaptive immunity, and several viral evasion mechanisms that may allow us to better understand these responses. A particular attention is paid to the possible collaboration of TLR and RLR sensors in anti-viral protection.

Keywords: Pattern recognition receptors; cross-talk; dendritic cell subsets; inflammation; interferon.

Figure 1

RLR-mediated pathways of type I interferon and inflammatory responses. The interaction of dsRNA as a viral genome or as a replication intermediate of RNA viruses with the helicase domain of RLRs (RIG-I or MDA5) induces association of the CARD domains of RIG-I/MDA5 and the adaptor protein IPS1 localized to the mitochondrial membrane. This receptor-adaptor interaction results in the activation of TBK1 and the subsequent phosphorylation of IRF3 and IRF7 on specific serine residues, resulting in their homodimerization. These dimers can translocate to the cell nucleus and activate the transcription of type I IFN genes. The expression of IRF3, IRF7, RIG-I and MDA5 is coordinately upregulated by type I IFN-mediated signaling acting as an amplification circuit. This pathway together with IPS1 is coupled to the NF-κB signaling pathway through the interaction of FADD (FAS-associated via death domain), RIP1, and TRAF6 resulting in the induction of inflammatory cytokine genes, such as IL-1β, IL-6 and TNFα. The TRIM proteins shown act as specific regulators of this pathway.

Figure 2

The interplay of TLR and RLR signaling. TLRs expressed on the cell surface or localized on intracellular membranes recognize various sets of pathogenic structures among them viral genomes or replication intermediates and transduce signals through the NF-κB/type I IFN pathways. The TLR3 and TLR4 mediated signaling pathways are independent of MyD88 and IRAKs (IRAK-1/2/4), whereas the other TLRs use the MyD88 pathway. TLR4 is capable of using both MyD88-dependent and independent signaling. TRAF3 and TRAF6 have a cardinal role in both the collaboration and the essential signaling processes of TLRs and RLRs.