Toll-like receptors: a family of pattern-recognition receptors in mammals

Abstract

The innate immune system uses a variety of germline-encoded pattern-recognition receptors that recognize conserved microbial structures or pathogen-associated molecular patterns, such as those that occur in the bacterial cell-wall components peptidoglycan and lipopolysaccharide. Recent studies have highlighted the importance of Toll-like receptors (TLRs) as a family of pattern-recognition receptors in mammals that can discriminate between chemically diverse classes of microbial products. First identified on the basis of sequence similarity with the Drosophila protein Toll, TLRs are members of an ancient superfamily of proteins, which includes related proteins in invertebrates and plants. TLRs activate innate immune defense reactions, such as the release of inflammatory cytokines, but increasing evidence supports an additional critical role for TLRs in orchestrating the development of adaptive immune responses. The sequence similarity between the intracellular domains of the TLRs and the mammalian interleukin-1 and interleukin-18 cytokine receptors reflects the use of a common intracellular signal-transduction cascade triggered by these receptor classes. But more recent findings have demonstrated that there are in fact TLR-specific signaling pathways and cellular responses. Thus, TLRs function as sentinels of the mammalian immune system that can discriminate between diverse pathogen-associated molecular patterns and then elicit pathogen-specific cellular immune responses.

Figure 1

Structural features of human members of the TLR protein family and the archetypal Drosophila Toll protein. Toll and its relatives are characterized by an amino-terminal extracellular leucine-rich repeat (LRR) domain, which is probably involved in ligand binding, and an intracellular Toll/interleukin-1 receptor (TIR) domain required for signal transduction. Known ligands of different TLRs and chromosomal locations of the human TLR genes are indicated. Red arrows indicate a possible dimerization between TLR1, TLR2 and TLR6. TLR9 is normally expressed intracellularly. Abbreviations: MALP-2, macrophage-activating lipopeptide-2; LAM, lipoarabinomannan; details of other ligands mentioned in the figure are discussed in the text.

Figure 2

TLR signal transduction pathways. All TLR proteins utilize the adapter protein MyD88 to activate a signaling pathway leading to the activation of MAP kinases and the transcription factor NF-κB in a TRAF-6-dependent manner. These signaling events culminate in expression of the pro-inflammatory cytokines IL-1β and TNF-α. TLR4 uses an additional adapter molecule, called TIRAP or Mal, to induce the expression of IL-6 and IFN-β. Via an autocrine/paracrine mechanism, IFN-β engages the type I IFN receptor (IFNAR), which leads to the activation of the Jak and Tyk kinases. These kinases phosphorylate the transcription factor STAT1 at tyrosine 701 and serine 727, thus allowing STAT1 to translocate to the nucleus. Nuclear STAT1, together with NF-κB, activates the STAT1-dependent genes inducible nitric oxide synthase (iNOS) and IFN-γ-inducible protein (IP-10). The + symbols indicate that the two contributing signal transduction pathways must be triggered concomitantly in order to get gene activation.