Toll Like Receptors and Their Ligands

The first line of immune response in mammals against microbial pathogens is the recognition of pathogen-associated molecular patterns by TLR family members. As the cornerstone for initiating innate immune responses, the TLR pathogen recognition system is evolutionarily conserved. The Toll protein was originally identified in Drosophila as a receptor playing a key role in development, as well as in antifungal responses. In mammals, at least eleven TLRs have been reported and most of these receptors have been linked to recognition of specific pathogen-associated ligands. Based on the cytoplasmic domains of Drosophila Toll and some mammalian TLRs, they are also homologous to members of the IL-1 receptor (IL-1R) family. Furthermore, the intracellular domains of TLRs and IL-1R are homologous to a region in the plant R gene product, thus designating these regions as "TIR" domains (6,10).

Signaling mechanisms mediated by TIR domains are remarkably similar amongst different organisms and various TLR/IL-1R family proteins. The apical signaling adap-

Fig. 4. TLRs and their ligands. See Subheading 2. for more details.

tors that are directly recruited to Drosophila Toll or mammalian TLR/IL-1R also contain TIR domains that interact with the receptors through their TIR counterparts. Here, we will first describe various TLRs and their specific ligands (Fig. 4) (6,11) and functions based on biochemical and genetic studies. In the next section, we will focus on TIR-containing adaptors and other key signaling molecules.

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