Toll-like receptor
Toll-like receptors (TLRs) are primary transmembrane proteins of immune cells that serve as a key part of the innate immune system; in addition they show a link between the innate and adaptive immune systems in vertebrates. They are a group of pattern recognition receptors (PRRs) that bind to pathogen-associated molecular patterns (PAMPs). They were first discovered in the fruit fly Drosophila melanogaster, but they have close homologues in mammalian immune cells. Their function is the recognition of pathogens and the activation of immune cells directed against those pathogens.
Their name derives from sequence homology to the Drosophila melanogaster gene Toll. In flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. Later, Toll was found to have a role in the fly's immunity to funguses. This last fact was discovered at about the time Toll-like receptors were identified in mammals.
There are 11 Toll-like receptors (named very simply e.g. TLR1 - TLR11) that have been identified in mammalian systems, not all are present in humans, and some are not present in mice (the main experimental model).
In addition non-mammalian TLRs exist in other vertebrates (inc. goldfish and chickens) and their exact relationship with mammalian TLRs is still undetermined.
Nevertheless the function of TLRs in all organisms appears to be similar enough to use a single model of action. Each Toll-like receptor works as either a homodimer or heterodimer in the recognition of a specific or set of specific molecular determinants present on microorganisms.
Because the specificity of Toll-like receptors (and other innate immune receptors), the receptors must recognize determinants that are expressed and are not subject to mutation in the microorganisms, while not being present on the host.
Thus, TLRs recognize molecules or parts of molecules in the pathogenic organisms that are extremely well conserved.
Well conserved features include bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides and lipoarabinomannan; proteins such as flagellin from bacterial flagella; double-stranded RNA of viruses or the unmethylated CpG islands of bacterial and viral DNA; and certain other RNA and DNA.
Following activation by the bound pathogenic factor, several reactions are possible. In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Another possible reaction is the production of other signalling factors which trigger inflammation.
The discovery of the Toll-like receptors finally identified the innate immune receptors that were responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seem only to be involved in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms.
More recently TLRs have been suspected of binding too non-pathogen assocaited factors produced during disease, stress, and trauma; including molecules such as fibrinogen (involved in blood clotting post-trauma) and heat shock proteins (HSPs) (generated in heats tress, inc. pathogen response fevers). The hypothesis (aka The Danger Model of immunity) is that these molecular signatures are recognised as associated with either an increased risk of disease, or disease itself, and put the immune system on alert through TLR activation. This model is still not entirely accepted by science as yet, and may even be considered by some as fringe lunacy.
References
- Daniel R Goldstein, "Toll-like receptors and other links between innate and acquired alloimmunity", Current Opinion in Immunology 16(5):538-544, October 2004 (doi:)
