Toll like receptors
Toll-Like Receptors (TLRs)
Overview
Toll-like receptors (TLRs) are a class of proteins that play a crucial role in the innate immune system. These single-spanning receptors are primarily expressed on sentinel cells, including macrophages and dendritic cells, and are responsible for recognizing structurally conserved molecules derived from microbes. They activate immune cell responses upon detecting these microbes at physical barriers such as the skin or mucosal tracts of the intestines.
Known TLR Types:
TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, TLR13.Humans do not possess genes for TLR11, TLR12, and TLR13, while mice lack a functional gene for TLR10.TLRs are located both on the cell membrane (TLR1, TLR2, TLR4, TLR5, TLR6, TLR10) and in intracellular vesicles (TLR3, TLR7, TLR8, TLR9), which act as sensors for nucleic acids.
Function
TLRs enable the immune system to identify pathogen-associated molecular patterns (PAMPs). The engagement of a TLR with its ligand, whether from a vaccine adjuvant or from a pathogen, is foundational to initiating immune responses and developing antigen-specific acquired immunity.
Upon activation, TLRs recruit adaptor proteins to trigger a cascade of signaling pathways that activate downstream proteins, including various protein kinases. This results in the modulation of gene expression, leading to cytokine production, cell proliferation, and survival, contributing to both innate and adaptive immunity. For instance, recognition of bacterial factors may result in phagocytosis, while viral factors may prompt cell apoptosis and the release of antiviral molecules like interferons.
Superfamily and Structure
TLRs belong to the interleukin-1 receptor/toll-like receptor superfamily, characterized by a shared TIR domain. These receptors are pattern recognition receptors (PRRs) capable of binding both exogenous PAMPs and endogenous damage-associated molecular patterns (DAMPs). TLRs are conceptually categorized into three subgroups based on TIR domain structure and function.
Evolution and Distribution
TLRs are conserved across various species, including both vertebrates and invertebrates and appear to be some of the oldest components of the immune system. Research has also identified TLRs within the mammalian nervous system.
Summary of Mammalian TLRs by Function
Receptor | Ligand(s) | Ligand Location | Adaptor(s) | Cell Types |
TLR 1 | Multiple triacyl lipopeptides | Bacterial lipoprotein | MyD88/MAL | Monocytes, macrophages, B lymphocytes |
TLR 2 | Multiple glycolipids | Bacterial peptidoglycans | MyD88/MAL | Monocytes, macrophages, neutrophils |
TLR 3 | Double-stranded RNA, poly I:C | Viruses | TRIF | Dendritic cells, B lymphocytes |
TLR 4 | Lipopolysaccharide | Gram-negative bacteria | MyD88/MAL/TRIF/TRAM | Monocytes, macrophages, intestinal epithelium |
TLR 5 | Bacterial flagellin | Bacteria | MyD88 | Monocytes, macrophages |
TLR 6 | Multiple diacyl lipopeptides | Mycoplasma | MyD88/MAL | Monocytes, macrophages |
TLR 7 | Imidazoquinoline | Small synthetic compounds | MyD88 | Monocytes, macrophages |
TLR 8 | Small synthetic compounds, single-stranded Viral RNA | MyD88 | Monocytes, macrophages | |
TLR 9 | Unmethylated CpG Oligodeoxynucleotide DNA | Bacteria, DNA viruses | MyD88 | Monocytes, macrophages |
TLR 10 | Triacylated lipopeptides | Unknown | B cells, monocytes | |
TLR 11 | Profilin | Toxoplasma gondii | MyD88 | Monocytes, macrophages |
Signaling Pathways
TLRs utilize two primary signaling pathways: MyD88-dependent and TRIF-dependent pathways, each pivotal for the immune responses they mediate.
MyD88-dependent pathway: Utilized by most TLRs; activates NFκB and MAPK pathways upon ligand binding.
TRIF-dependent pathway: Utilized by TLR3 and TLR4; involved in the induction of type I interferons.
Medical Relevance
TLR agonists are being explored as vaccine adjuvants and in treatments for conditions like cancer. Drugs like imiquimod and resiquimod target TLR7/8 pathways for therapeutic benefit. TLR4 is implicated in opioid tolerance and addiction due to its role in inflammation.
Historical Context
The concept of TLRs emerged as scientists identified the need for receptors capable of detecting unique microbial molecules. The prototypic toll receptor in Drosophila melanogaster was discovered in the 1980s and has since become integral to our understanding of immune response in mammals.