Toll-like receptor

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles (because they are sensors of nucleic acids).

TLRs received their name from their similarity to the protein coded by the toll gene.

The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and non-immune cells (epithelial and endothelial cells, and fibroblasts).

The binding of ligands — either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection — to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.

Upon activation, TLRs recruit adaptor proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity. If the ligand is 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.

Toll-like receptors have also been shown to be an important link between Innate immune system and adaptive immune system through their presence in dendritic cells. Flagellin, a TLR5 ligand, induces cytokine secretion on interacting with TLR5 on human T cells.

TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). In addition to the recognition of exogenous PAMPs, TLRs can also bind to endogenous damage-associated molecular patterns (DAMPs) such as heat shock proteins (HSPs) or plasma membrane constituents. TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the "interleukin-1 receptor / toll-like receptor superfamily"; all members of this family have in common a so-called TIR (toll-IL-1 receptor) domain.

Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for interleukins that are produced by macrophages, monocytes, and dendritic cells and all have extracellular Immunoglobulin (Ig) domains. Proteins with subgroup 2 TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin. A third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2.