Toll-like receptors in humans

The innate immune system senses invading microorganisms by a phylogenetically conserved family of proteins PRRs of which TLRs are ones of the most important. There are at least 10 different TLRs in humans and 11 in mice. They have in the course of evolution specialized for the recognition of conserved structures among microorganisms called PAMPs. Activation of TLRs results in induction of innate immunity mechanisms as well in development of antigen-specific adaptive immune responses, thus bridging innate and adaptive immunity. The role of the immune system is to detect and eliminate invading pathogens by means of discrimination between self and non-self antigens. The immune system in mammals can be divided into innate and adaptive immunity. The phylogenetically newer adaptive immunity detects self and pathogenic antigens using receptors that are expressed on the surface of B and T cells. Through immunoglobulin and T-cell receptor gene rearrangement, B and T cells produce more than 1011 unique antigen receptors, respectively. This approach allows the adaptive immune system to respond to an immense variety of different antigens. This elaborate system can be found in vertebrates only and represents a potent mechanism in fighting microbial infections. On the other hand, the innate immune system is present in all multi-cellular organisms and is phylogenetically conserved. In contrast to the system of adaptive immunity, which was in the focus of scientific interest in the past years, less effort was made to study the mechanisms of innate immunity, which remained unclear until recently. The identification of Toll-like receptors (TLRs) has brought more understanding on the mechanisms by which the innate immune system recognizes non-self and how important role TLRs play in detection of invading pathogens. According to the recent evidence, TLRs belong to a family of pattern recognition receptors (PRRs) that recognize conserved parts of microbial components (PAMPs – pathogen-associated molecular patterns). Toll-like receptors in humans The first recognized mammalian TLR homologue of the drosophila Toll (Belvin and Anderson, 1996) was TLR4, identified in 1997, just a year after elucidating the role of the drosophila Toll in fighting fungal infection (Medzhitov et al., 1997). In the following years, more proteins structurally and functionally related to the drosophila Toll and recognizing a whole array of microbial structures were discovered, creating a family referred to as the TLRs (Table 1). Like drosophila Toll, human TLRs are type I transmembrane proteins with an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic carboxy-terminal Toll-interleukin 1 receptor (TIR) domain (Fig. 1). Based on the chromosomal localization, genomic structure and amino acid sequences, the human TLRs can be divided into five subfamilies: TLR2, TLR3, TLR4, TLR5, and TLR9. The TLR2 subfamily consists of TLR1, TLR2, TLR6, and TLR10, the TLR9 subfamily is composed of TLR7, TLR8, and TLR9. TLR3, TLR4, and TLR5 are represented only by one family member, respectively. TLR1 and TLR6 genes are located closely to 4p14, TLR2 maps to 4q32, while TLR3 is located near TLR2, at 4q35. TLR4 resides on 9q33-35, whereas TLR5 is at 1q33.3 (Rock et al., 1998; Takeuchi et al., 1999). TLR7 and TLR8 are located as a tandem in Xp22, TLR9 maps to 3p21.3 (Du et al., 2000). Toll-like receptor 4 and its ligands The first ligand for TLR4 was identified in 1998. It was shown that the mammalian TLR4 protein had been Received August 18, 2005. Accepted September 21, 2005. The study was supported by the Research Programs of the Ministry of Education of the Slovak Republic: VEGA 1/0543/03. Corresponding author: Milan Buc, Department of Immunology, Comenius University School of Medicine, Sasinkova 4, 811 08 Bratislava 1, Slovakia, e-mail: [email protected]. Abbreviations: DCs – dendritic cells, ds – double-stranded, IFN – interferon, IL – interleukin, LAM – lipoarabinomannan, LPS – lipopolysaccharide, MHC – major histocompatibility complex, OspA – outer-surface lipoprotein, PAMPs – pathogen-associated molecular patterns, pDCs – plasmacytoid DCs, PRRs – pattern recognition receptors, ss – single-stranded, TLRs – Toll-like receptors. Review Toll-like Receptors. I. Structure, Function and Their Ligands ( dendritic cells / Gram-positive and Gram-negative bacteria / lipopolysaccharide / PAMPs / PRRs / TLRs / TH-cell polarization / viruses )