Transmembrane Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) are transmembrane PRRs located on plasma or internal membranes (endosomes, endoplasmic reticulum, lysosomes).

TLRs are a family of evolutionary conserved pattern recognition receptors (PRRs) expressed by various cell types, particularly those of the innate immune system. Ten functional TLRs have been identified in humans while twelve have been identified in mice. TLRs are type I membrane glycoproteins, characterised by a cytoplasmic TIR (Toll/interleukin-1 receptor (IL-1R)) domain and a leucine-rich repeat domain. They can detect exogenous pathogen associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipopeptides, proteins or nucleic acids derived from bacteria, fungi, viruses or parasites, as well as endogenous, host-derived danger associated molecular patterns (DAMPs), including HMGB1 and b-defensins. The binding of an agonist to a TLR results in the dimerisation of receptor TIR domains, which leads to the differential recruitment of adapter proteins containing also a TIR domain, MyD88, MAL, TRIF and TRAM. MyD88 and TRIF allow to mediate the interaction to downstream kinases, while MAL and TRAM translocate MyD88 or TRIF to the activated TLRs. This results in the activation of a number of downstream signalling pathways, including NF-κB, MAPK and IRF pathways. The activation of these signalling pathways results in the production and release of various cytokines and chemokines. TLRs play a crucial role in host defence and inflammation and are implicated in the pathogenesis of immune diseases and cancer.

CLRs are PRRs that recognise carbohydrate ligands. The C-type designation is from their requirement for binding of calcium. This is a large family of proteins containing a signal transmembrane domain, and is divided into 17 groups based on functional and structural characteristics. Members of this receptor family contain a carbohydrate recognition domain (CRD), which mediates binding of the receptor to its carbohydrate ligand. Some of CLRs function as PRRs for the recognition of microbial components and internalise various glycoproteins and microbes for the purposes of clearance and antigen presentation to T lymphocytes. These CLRs bind to carbohydrate ligands and induce multiple signalling cascades, which lead to the activation of several transcription factors including NF-κB and induce inflammatory responses.

Cell Surface TLRs

TLR1, 2, 4, 5, 6 and 10 are present at the cell surface and recognise bacterial and fungal products. All those TLRs are conserved in human and mice except TLR10 that is only present in humans. In mice TLR11 is expressed instead of the human TLR10.

Intracellular TLRs

Intracellular TLRs are localised in endosomes and include TLR3, TLR7, TLR8, TLR9, TLR11 (expressed only in mice), TLR12 and TLR13. They recognise nucleic acids from bacteria and viruses in physiological conditions but can also recognise self-nucleic acids in auto-immune pathological conditions ¹³. TLR3 recognises double stranded DNA (dsDNA) from viruses but also small interfering RNAs and self RNAs derived from damaged cells ^{14, 15, 16}. TLR7 and TLR9 are expressed in plasmocytoid dendritic cells (pDC). TLR7 can recognise virus single stranded RNA (ssRNA) but also RNA from Streptococcus B bacteria in conventional DCs whereas TLR9 can sense viral and bacterial DNA rich in unmethylated CpG-DNA motifs but also hemozoin from Plasmodium falciparum ¹⁷. TLR8 recognises viral and bacterial RNA and TLR13 seems to react with bacterial 23S rRNA as well as unknown components of VSV (Vesicular Stomatitis Virus).

CLRs - C-type Lectin Receptors

CLRs are PRRs that bind carbohydrates in a calcium-dependant manner. They can be divided into two groups of transmembrane receptors and one group of soluble receptors. The first group of membrane CLR (Type I) contains receptors with several CRD or CRD-like domains when Type II group of CLRs is composed of receptors with only one domain. They recognise glycan structures on pathogens and endogenous glycoproteins and facilitate the routing of internalised antigen to various MHC class I or II compartments (depending on the CLR involved) for further presentation to T lymphocytes ¹⁹. The most documented CLRs are those of the type II group that includes Dectin-1 & -2, Mincle or DC-SIGN. Dectin-1 recognises PAMPs like b-glucan in fungal cell walls and is expressed by macrophages, DCs and neutrophils. Other CLRs recognise mannan ²⁰.