Toll-like receptor
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Toll-like receptors (TLRs) are primary transmembrane proteins of immune cells that serve as a key part of the innate immune system, which recognizes perpetual infectuous threats. Their activation stimulates the innate responses of immune cells to these threats. In vertebrates, they are also able to stimulate activation of the adaptive immune system, linking innate and acquired immune responses. TLR are considered pattern recognition receptors (PRRs), binding to pathogen-associated molecular patterns (PAMPs), small molecular sequences consistently found on pathogens. Their function is the recognition of pathogens and the activation of immune cell responses directed against those pathogens.
First discovered in the fruit fly Drosophila melanogaster, TLRs are present in mammalian immune cells as well as in numerous other animals (including goldfish and chickens). They have even been found in plants and are thus believed to have an ancient evolutionary origin; after the defensins, they may be the oldest components of the immune system.
Their name derives from sequence homology to the Drosophila melanogaster gene Toll. ("Toll" is German for "amazing" or "mad".) In flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. In 1996, Toll was found to have a role in the fly's immunity to fungal infections. Toll-like receptors in mammals were identified in 1997.
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Receptors
It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptors. Eleven (named simply TLR1 to TLR11) have been identified in humans, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. Other mammals may express TLR which are not found in humans. This may complicate the process of using experimental animals as models of human innate immunity.
The function of TLRs in all organisms appears to be similar enough to use a single model of action. Each Toll-like receptor forms 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) cannot be changed, these receptors must recognize patterns that are constantly present on threats, not subject to mutation, and highly specific to threats (e.g. not normally found in the host where the TLR is present.) Patterns that meet this requirement are usually critical to the pathogen's function and cannot be eliminated or changed through mutation; they are said to be evolutionarily conserved. Well conserved features in pathogens 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. See the table below for a summary of known TLR activity.
| Receptor | Ligand PAMP(s) | Activation Cascade(s) |
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| TLR 1 | triacyl lipoproteins | unknown |
| TLR 2 | lipoproteins; gram positive peptidoglycan; lipoteichoic acids; fungal hyphae and conidia | MyD88 dependent TIRAP |
| TLR 3 | double-stranded RNA (from viruses) | MyD88 independent TRIF/TICAM |
| TLR 4 | lipopolysaccharide | MyD88 dependent TIRAP; MyD88 independent TRIF/TICAM/TRAM |
| TLR 5 | flagellin | MyD88 dependent IRAK |
| TLR 6 | diacyl lipoproteins | unknown |
| TLR 7 | small synthetic compounds; single-stranded RNA | MyD88 dependent IRAK |
| TLR 8 | small synthetic compounds | MyD88 dependent IRAK |
| TLR 9 | unmethylated CpG DNA | MyD88 dependent IRAK |
| TLR 10 | unknown | unknown |
| TLR 11 | unknown, but present in uropathogenic bacteria | MyD88 dependent IRAK |
Activation and effects
Following activation by the bound pathogenic factor, several reactions are possible. Immune cells can produce signalling factors called cytokines which trigger inflammation. 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). Immune cells that have detected a virus may also release anti-viral factors such as interferons.
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.
Danger model
More recently TLRs have been suspected of binding to non-pathogen associated 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 heat stress, including pathogen response fevers). This is based upon Polly Matzinger's "Danger Model" of immunity, which suggests that these molecular signatures are recognised as associated with either an increased risk of disease, or disease itself ("danger!"), and put the immune system on alert through TLR activation. However, this model is controversial.
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 (Template:DOI)
- Luke A. J. O'Neill, "Immunity's Early-Warning System", Scientific American 292(1):38-45, January 2005
- Dunne A, O'Neill LA, "The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense", Sci STKE. 2003 Feb 25;2003(171):re3. online version (http://itsa.ucsf.edu/~micro/pathogenesis/docs/tlr_review.pdf)