Nucleic acid-sensing TLRs: trafficking and regulation

Highlights • Nucleic acid-sensing TLRs are regulated at multiple levels to maintain immunological tolerance to host-derived ligands. • The recently solved crystal structures of TLR7, TLR8, and TLR9 provide evidence for the need of proteolytic processing and the mode of ligand binding. • TLR7 and TLR8 are dual receptors for single nucleosides and short ssRNA oligoribonucleotides. • The need for ligand processing to generate stimulatory nucleic acid fragments emerges as a new principle for TLR activation.