In 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:
- Toll-like receptors (TLR)
- Nucleotide oligomerisation receptors (NLR)
- C-type lectin receptors (CLR)
- RIG-1 like receptors (RLR)
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 called pathogen 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).
- TLR1, 2, 4 and 6 recognise bacterial lipids
- TLR3, 7 and 8 recognise viral RNA
- TLR9 recognises bacterial DNA
- TLR5 and 10 recognise bacterial or parasite proteins
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 different signalling 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.
- TLR 1,2,4,5,6,7,8 and 9 use MYD88
- TLR 3 and 4 use TRIF
In addition, TLR1, 2, 4 and 6 need a second adaptor called TIRAP to recuit MYD88 and TLR4 needs TRAM to recruit TRIF. These adaptors recruit several proteins, such as kinases,which initiate different signalling cascades.
Three main pathways are activated by TLRs:
- MAP kinase pathway (ERK, p38 and JNK)
- NFkB pathway
- IRF pathway
TLR-mediated signalling pathways lead to the translocation of transcription factors, such as NFkB and IRFs 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:
- Pro-inflammatory cytokines such as IL-6, TNFa and IL-12
- Anti-inflammatory cytokines such as IL-10
(These cytokines shape the T-cell response)
- Type I IFNs which are involved in anti-viral responses
- Chemokines which attract other immune cells to the site of infection
- Chemokine receptors which, for example, allow TLR-activated cells to migrate to lymph nodes
- Anti-microbial molecules
- Co-stimulatory molecules such as CD80/86 and CD40 which are involved in T-cell activation by antigen presenting cells
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.