TLR3

TLR3 (Toll-like receptor 3) is a member of the Toll-like receptor family of pattern recognition receptors in the innate immune system. It detects double-stranded RNA, a molecular pattern associated with viral infections, and initiates antiviral immune responses.

TLR3 is a type I transmembrane protein with leucine-rich repeats in the extracellular domain and a Toll/IL-1 receptor (TIR) signaling domain in the cytoplasm. It is predominantly localized to endosomal membranes within dendritic cells, macrophages, epithelial cells, and some glial cells, where it encounters dsRNA generated during viral replication.

Upon binding dsRNA, TLR3 recruits the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β), activating downstream kinases TBK1 and IKKε. This leads to phosphorylation and nuclear translocation of IRF3 and activation of NF-κB, triggering transcription of type I interferons (IFN-α/β) and proinflammatory cytokines such as TNF and IL-6. The signaling can also promote autophagy and enhanced antigen presentation, contributing to antiviral defenses and shaping adaptive immunity.

Biological significance: TLR3 plays a role in defense against a range of RNA viruses and influences dendritic cell maturation and T cell priming. Regional differences in expression and signaling can influence infectious and inflammatory outcomes.

Clinical relevance: Rare inherited defects in TLR3 signaling have been linked to susceptibility to herpes simplex encephalitis, underscoring a protective role in the central nervous system. TLR3 agonists, notably synthetic double-stranded RNA analogs such as poly(I:C), have been explored as vaccine adjuvants and cancer therapeutics, while antagonists are studied to limit harmful inflammation.