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n order to detect pathogens such as bacteria and viruses the immune system is equipped with receptors called pattern recognition receptors (PRRs) that are specialised in their recognition. These receptors are a key element of the innate immune system. They are mainly expressed by antigen presenting cells such as dendritic cells and macrophages, but they are also found in other immune and non-immune cells.

The PRR are divided in four families:

These receptors are strategically localised in the cell (Figure 1). There are present at the cell surface to recognise extracellular pathogens such as bacteria or fungi, in the endosomes where they sense intracellular invaders such as viruses and finally in the cytoplasm.

These receptors recognise conserved molecular structures of pathogens (Figure 2). These motifs calledpathogen associated molecular patterns (PAMPs) are specifc to the micro-organism and essential for its viability.

Toll-like receptors (TLRs) are so far composed of 11 members in mammals named TLR1 to 11. They are specialised in the recognition of conserved molecular structures in bacteria, viruses, fungi and parasites. Each TLR has a broad range of specifities (Figure 3).

TLRs are type I transmembrane receptors composed of an extracellular domain involved in the recognition of the microbial product, and a TIR domain in the cytoplasmic tail that recruits differentsignalling molecules that will in turn activate the transcription of genes involved in inflammation and in anti-microbial defences. Each TLR tailors the immune response to the pathogen that they sense.

TLR signalling initiates with the recruitment of adaptors proteins to their cytoplasmic tail.

There are two main adaptors: MYD88 and TRIF.

In addition, TLR124 and 6 need a second adaptor called TIRAP to recuit MYD88 and TLR4 needs TRAMto recruit TRIF. These adaptors recruit several proteins, such as kinases,which initiate different signalling cascades.

Three main pathways are activated by TLRs:

TLR-mediated signalling pathways lead to the translocation of transcription factors, such as  NFkB andIRFs in the nucleus, where they activate the transcription of several genes involved in the immune response which eventually result in the elimination of the pathogen.

The following are some of the elements induced upon TLR stimulation:

(These cytokines shape the T-cell response)

TLR signalling is also important for enhancing antigen uptake and presentation.

Despite the different TLRs having several signalling pathways in common they are nonetheless able to tune the quality, the intensity and the duration of each of these signalling cascades to generate an immune response specific for the pathogen they are sensing.

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- 05/09/2014

 

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