Medicina

RevIeW

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors
© 2010 Nature America, Inc. All rights reserved.

Taro Kawai1,2 & Shizuo Akira1,2
The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immuneresponses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identifiedcytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
During the past decade, there has been rapid progress in the understanding of innate immune recognition of microbial components and its critical role in host defense against infection. Theearly concept of innate immunity was that it nonspecifically recognized microbes; however, the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associatedmolecular patterns (PAMPs)1,2. TLRs are type I transmembrane proteins with ectodomains containing leucine-rich repeats that mediate the recognition of PAMPs; transmembrane domains; and intracellular Toll–interleukin 1 (IL-1) receptor (TIR) domains required for downstream signal transduction. So far, 10 and 12 functional TLRs have been identified in humans and mice, respectively, with TLR1–TLR9being conserved in both species. Mouse TLR10 is not functional because of a retrovirus insertion, and TLR11, TLR12 and TLR13 have been lost from the human genome. Studies of mice deficient in each TLR have demonstrated that each TLR has a distinct function in terms of PAMP recognition and immune responses3. Elucidation of the crystal structure of several TLR ectodomains has provided structuralinsights suggesting that several PAMPs act as ‘ligands’ for TLRs4. PAMPs recognized by TLRs include lipids, lipoproteins, proteins and nucleic acids derived from a wide range of microbes such as bacteria, viruses, parasites and fungi3. The recognition
1Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, and 2Department of Host Defense, Research Institute forMicrobial Diseases, Osaka University, Osaka, Japan. Correspondence should be addressed to S.A. (sakira@biken.osaka-u.ac.jp).

Published online 20 April 2010; doi:10.1038/ni.1863

of PAMPs by TLRs occurs in various cellular compartments, including the plasma membrane, endosomes, lysosomes and endolysosomes3. The proper cellular localization of TLRs is thought to be important for ligandaccessibility, the maintenance of tolerance to self molecules such as nucleic acids and downstream signal transduction. TLR signaling pathways were intensively studied after the discovery of the TIR domain–containing adaptor molecule MyD88. The subsequent identification of additional TIR domain–containing adaptors has shown that individual TLRs selectively recruit distinct adaptor molecules, providingspecific immunological responses tailored to the infecting microbes3. Studies have indicated that there are cell type–specific signaling pathways that define their immunological properties. For example, plasmacytoid dendritic cells (pDCs) and inflammatory monocytes have unique signaling pathways that govern antiviral responses that are probably absent in other cell types5,6. Recently, much attention...