Fig. 3.10 Innate immune recognition by Toll-like receptors. Each of the human or mouse TLRs whose specificity is known recognizes one or more microbial molecular patterns, generally by direct interaction with molecules on the pathogen surface. Some Toll-like receptor proteins form heterodimers (e.g., TLR-1:TLR-2 and TLR-6:TLR-2). LPS, lipopolysaccharide.
of Spätzle. In this sense Toll is not a classical pattern recognition receptor. However, X-ray crystal structures of several mammalian dimeric TLRs bound to their ligands show that at least some mammalian TLRs make direct contact with microbial ligands.
Fig. 3.11 The cellular locations of the mammalian Toll-like receptors.
TLRs are transmembrane proteins whose extracellular region contains 18–25 copies of the leucine-rich repeat (LRR), but these cartoons depict only 9 LRRs for simplicity. Some TLRs are located on the cell surface of dendritic cells, macrophages, and other cells, where they are able to detect extracellular pathogen molecules. TLRs are thought to act as dimers. Only those that form heterodimers are shown in dimeric form here; the rest act as homodimers. TLRs located intracellularly, in the walls of endosomes, can recognize microbial components, such as DNA, that are accessible only after the microbe has been broken down. The diacyl and triacyl lipopeptides recognized by the heterodimeric receptors TLR-6:TLR-2 and TLR-1:TLR-2, respectively, are derived from the lipoteichoic acid of Gram-positive bacterial cell walls and the lipoproteins of Gram-negative bacterial surfaces.
Mammalian TLR-1, TLR-2, and TLR-6 are cell-surface receptors that are activated by various ligands, including lipoteichoic acid and the diacyl and triacyl lipoproteins of Gram-negative bacteria. They are found on macrophages, dendritic cells, eosinophils, basophils, and mast cells. Ligand binding induces the formation of heterodimers of TLR-2 and TLR-1, or of TLR-2 and TLR-6. The X-ray crystal structure of a synthetic triacyl lipopeptide ligand bound to TLR-1 and TLR-2 shows exactly how it induces dimerization (Fig. 3.12). Two of the three lipid chains bind to the convex surface of TLR-2, while the third binds to the convex surface of TLR-1. Dimerization brings the cytoplasmic TIR domains of the TLR chains into close proximity with each other to initiate signaling. Similar interactions are presumed to occur with the diacyl lipopeptide ligands that induce the dimerization of TLR-2 and TLR-6. The scavenger receptor CD36, which binds long-chain fatty acids, and Dectin-1, which binds β-glucans (see Section 3-1), both cooperate with TLR-2 in ligand recognition.
TLR-5 is expressed on the cell surface of macrophages, dendritic cells, and intestinal epithelial cells; it recognizes flagellin, a protein subunit of bacterial flagella. TLR-5 recognizes a highly conserved site on flagellin that is buried and inaccessible in the assembled flagellar filament. This means that the receptor is activated only by monomeric flagellin, which is produced by the breakdown of flagellated bacteria in the extracellular space. Mice, but not humans, express TLR-11 and TLR-12, which share with TLR-5 the ability to recognize an intact protein. TLR-11 is expressed by macrophages and dendritic cells, and also by liver, kidney, and bladder epithelial cells.