Toll-like receptors

Christiane Nüsslein-Volhard, 1985

The gene product "Toll", which was primarily described in fruit flies, gave its name to these pathogen recognition receptors (PAMPs). The decisive indication of the function of the Toll protein was the observation that fruit flies without "Toll" cannot defend themselves against the fungus Aspergillus fumigatus. Humans (like other mammals) have Toll-like receptors, which can be activated by the binding of PAMPs.

In evolutionary terms, TLRs (TLR stands for"Toll-like receptor") are old, conserved PRRs (Pattern Recognition Receptors). Toll-like receptors are primarily used to recognize so-called "pathogen associated molecular patterns"(PAMPs).

TLRs are transmembrane glycoproteins. Their extracellular, N-terminal domain consists of an LRR that specifically binds different ligands. This is followed by a transmembrane domain. Signal transduction takes place through the cytoplasmic "Toll-interleukin-1 receptor homology" domain, TIR for short. This domain recruits molecules that also contain a TIR domain, but can differ from TLR to TLR.

In the meantime, 10 (TLR-1 to 10) have been described in humans. 6 of the human TLRs bind PAMPs extracellularly (TLR-1, 2, 4, 5, 6, 10) while 4 are only localized intracellularly (TLR-3, 7, 8 and 9). TLRs are expressed by immune cells of the innate and also by cells of the adaptive immune system (B and T cells) as well as by numerous non-immune cells, including keratinocytes. This wide distribution makes TLRs an excellent tool for the innate and acquired immune system. TLRs thus ensure the recognition of pathogens and the activation of antigen-specific acquired immunity. The activity of TLRs enables the innate defense mechanisms (see below Immunity, innate) to differentiate between "self" and "foreign". When recognizing pathogens, the various TLRs require different adaptor molecules to activate intracellular signalling cascades such as: MyD88, TICAM-1 (TRIF), TIRAP/MAL, TRAM, and SARM.

TLRs also play a supporting role in nickel allergy.

The key factors "C3a" and "C5a" of the complement system attract macrophages and neutrophil granulocytes. These carry TLR-type receptors on their surface. These receptors have an extracellular (leucine rich repeats. LRR-domain) and an intracellular TIR-domain (Toll-IL-1 receptor homologous domain). The extracellular domain is used for ligand binding, while the intracellular domain leads to signal transduction.

All Toll-like receptors (with the exception of TLR3) have the adapter protein MyD88 (myeloid differentiation primary response gene 88) in common. They associate with IRAK (IL-1 receptor-associated kinase) via this adapter protein. This process leads to the translocation of IRFs and NF-kappa B. TLR3, on the other hand, binds to TRIF (TIR-domain-containing adapter-inducing interferon-beta).

IRFs and NF-kappaB initiate the transcription of pro-inflammatory cytokines interleukin-1beta, interleukin-6, interleukin-12p70, interleukin-23 and TNF-alpha as well as type I interferons (IFN-alpha and interferon-beta).

This leads to the phosphorylation and thus activation of intracellular kinases (see MAP kinases below), whose task is the phosphorylation of intracellular inhibitors of transcription factors. Phosphorylation causes the inhibitor to lose its inhibitory effect. It releases its transcription factor, which is translocated into the cell nucleus where it regulates the expression of genes involved in the defense against infection. Imiquimod, for example, is a ligand for TLR7 and TLR8.

TLRs are found in all vertebrates, but also in simple organisms. TLRs recognise different functional components of viruses, bacteria and fungi and can thus trigger biochemical reaction chains in the cells that serve to defend against these pathogens. TLRs can also detect internal dangers, for example, those that arise from tissue damage. Here, the body's own molecules bind the TLRs. These signal molecules are called DAMP (danger associated molecular pattern).

The name "Toll-like receptor" is derived from a protein in Drosophila melanogaster called Toll. "Toll" was initially thought to be a gene product that is important for the development of the dorso-ventral axis in Drosophila embryos. Tolllike receptors (TLRs) consist of proteins that are similar to Toll, i.e. "Toll-like".

1. Lemaitre B et al (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: 973-983
2. Rad R et al (2007) Toll-like receptor-dependent activation of antigen-presenting cells affects daptive immunity to Helicobacter pylori. Gastroenterology. 133: 150-163
3. Satoh M et al (2007) Association between toll-like receptor 8 expression and adverse clinical outcomes in patients with enterovirus-associated dilated cardiomyopathy. At Heart J 154: 581-858