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). 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.

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.

Receptors

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).

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. See the table below for a summary of known TLR activity.

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. This model is controversial. Time will tell whether it will be generally accepted by the scientific community.

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:10.1016/j.coi.2004.08.001 (http://dx.doi.org/10.1016/j.coi.2004.08.001))
• 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)