Toll-like receptors (TLRs) are transmembrane proteins that are usually found on sentinel cells (macrophages, dendritic cells, natural killer cells, T-cells and B-cells, epithelial and endothelial cells) and are present in most vertebrates and invertebrates.
These proteins play a crucial role in the innate immune system, since they are responsible for recognizing pathogen-associated molecular patterns, or PAMPs (e.g., heat shock protein, bacterial lipoprotein, flagella, etc.), as these microorganisms enter the host’s body through the skin, mucous membranes, or intestinal tract mucosa.
How Do TLRs Work?
TLRs are capable of recognizing and binding with specific ligands, including viral double-stranded RNA, bacterial cell wall components, and other small molecules (e.g., anti-viral or immunomodulatory compounds).
What happens when the TLR binds with a specific ligand? Upon binding, the TLR activates the signaling transduction pathway, which then launches the appropriate immune and inflammatory response to counter the infection. During the process, the TLRs recruit adaptor proteins and other downstream proteins to upregulate or suppress the genes responsible for inflammatory responses and other transcriptional events.
This sequence of events will most likely lead to the production and proliferation of immunomodulatory cytokine proteins and the development of a strong antigen-specific acquired immunity.
If the infective agent is a bacterium, it may be phagocytosed and eventually ingested, but if the ligand is a viral factor, immune cells may release anti-viral factors, or the infected cell may undergo programmed cell death (apoptosis).
TLRs: Getting to Know the TLR Family
Most mammalian species have ten to fifteen types of TLRs. Humans and mice are known to have 13 TLRs each (TLR1 to TLR13). While the equivalent of most of these TLRs is present in most, but not all, mammalian species, some mammals may also have TLRs that are not found in humans.
Continuous research indicates that the TLR family is continuously growing. Currently, the vertebrate TLRs are divided into several families, grouped according to their similarities. The first group is composed of TLRs 1, 2, 6, 10, 14, and 15, the second has TLRs 7,8, and 9, and the third has TLRs 11, 12, 13, 16, 21, 22, and 23, while TLRs 3, 4, and 5 each are a class on their own.
TLRs can also be classified based on their location. Some are located on the cell membrane (TLRs 1, 2, 4, 5, and 6) while others can be found on the membrane of endosomes within the cell (TLRs 3, 7, 8, and 9).
Let’s get to know them individually.
TLR1
While TLR1 was first identified in the fruit fly (Drosophila melanogaster), research indicates that it is also present in human IL-1 receptors and is highly expressed in the spleen and peripheral blood cells. Since no ligand is directly identified for TLR1 and not much is known about it, except for the fact that it acts as a co-receptor for TLR2, its function largely remains a mystery.
TLR2 and TLR6
Because TLR2 (also known as CD282) works in cooperation with TLR1 and TLR6, it is not surprising to note that it can recognize a broad range of ligands, including bacterial lipoproteins, Gram-positive bacteria, and yeast cell walls.
TLR3
TLR3 is primarily associated in the recognition of viruses, since it activates the TRIF-dependent signaling pathway in the presence of retroviral double-stranded RNA.
TLR4
TLR4 acts as the principal receptor for LPS, a major component of the outer membrane of Gram-positive bacteria. LPS triggers a host of immunostimulatory responses and may cause endotoxin shock. TLR4 also recognizes several heat shock proteins from bacteria and host cells and fibrinogen, heparan sulfate fragments, and hyaluronic acid fragments from host cells.
TLR5
TLR5 is mostly expressed in the spleen, epithelial cells, and peripheral blood leukocytes and binds with flagellin from Gram-positive and Gram-negative bacteria.
TLR7 and TLR8
Human TLR7 and TLR8 recognize imidazoquinoline, a synthetic compound used to treat viral infections, specifically genital warts, while murine TLR7 can recognize loxoribine, a synthetic compound with anti-viral and anti-tumor activities.
TLR9
TLR9 can recognize between mammalian DNA and bacterial DNA. Upon stimulation, it activates the production of T-helper 1 cytokines.
TLR10
TLR10 recognizes triacylated lipopeptides, but its signaling pathway is not yet identified.
TLR11 and TLR12
These TLRs recognize profilin, an actin-binding protein present in the parasitic protozoan eukaryote that causes toxoplasmosis.
TLR13
Found mainly on the macrophages and conventional dendritic cells, TLR13 recognizes a specific ribosomal RNA sequence present in some bacteria and viruses.
While innate and adaptive immunity have always been considered as separate defense mechanisms against microbial infection, recent developments strongly indicate that TLRs can influence adaptive immune responses by inducing the maturation of dendritic cells, activating T-helper cells, and facilitating the expression of co-stimulatory molecules.