Assessment of the Toll-like receptor 3 pathway in endosomal signaling

The innate immune system plays key roles in antimicrobial responses by developing the pattern-recognition receptors that recognize microbial components. The endosomal Toll-like receptors (TLRs) and cytosolic RIG-I-like receptors (RLRs) both recognize viral nucleic acids and are essential for antiviral immunity. Recent evidence suggests that compartmentalization of the receptors, and also their adaptor molecule, is important for discrimination between self and nonself and for distinct innate immune signals. TLR3 is a type I transmembrane protein that localizes in the endosomal membrane in myeloid dendritic cells (DCs) and fibroblasts/epithelial cells. TLR3 recognizes extracellular viral double-stranded RNA (dsRNA) and the synthetic dsRNA, poly(I:C). On recognition of dsRNA in the endosomes, TLR3 oligomerizes and induces type I interferon and proinflammatory cytokine production via an adaptor molecule, TICAM-1 (also known as TRIF). Additionally, the TLR3 signal in DCs triggers gene transcription required for DC maturation and the activation of natural killer cells and cytotoxic T lymphocytes. Remarkably, it has been reported that extracellular dsRNA is also recognized by cytosolic RLR. Making a distinction between TLR3-mediated endosomal signaling and RLR-mediated signaling is key to understanding the role of these receptors in innate immunity.