Toll-like receptor 2 also known asTLR2 is aprotein that in humans is encoded by theTLR2gene.[5] TLR2 has also been designated asCD282 (cluster of differentiation 282). TLR2 is one of thetoll-like receptors and plays a role in theimmune system. TLR2 is amembrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.
The protein encoded by this gene is a member of thetoll-like receptor (TLR) family, which plays a fundamental role inpathogen recognition and activation ofinnate immunity. TLRs are highly conserved fromDrosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production ofcytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is expressed most abundantly in peripheral bloodleukocytes, and mediates host response toGram-positive bacteria[6] andyeast via stimulation ofNF-κB.[7]
In the intestine, TLR2 regulates the expression ofCYP1A1,[8] which is a key enzyme in detoxication of carcinogenicpolycyclic aromatic hydrocarbons such asbenzo(a)pyrene.[9]
The immune system recognizes foreignpathogens and eliminates them. This occurs in several phases. In the early inflammation phase, pathogens are recognized byantibodies that are already present (innate or acquired through prior infection; see alsocross-reactivity). Immune-system components (e.g.complement) are bound to the antibodies and kept near, in reserve to disable them viaphagocytosis by scavenger cells (e.g.macrophages).Dendritic cells are likewise capable of phagocytizing but do not do it for the purpose of direct pathogen elimination. Rather, they infiltrate thespleen andlymph nodes, and eachpresents components of anantigen there, as the result of which specific antibodies are formed that recognize precisely that antigen.
These newly formed antibodies would arrive too late in an acute infection, however, so what we think of as "immunology" constitutes only the second half of the process. Because this phase would always start too late to play an essential role in the defense process, a faster-acting principle is applied ahead of it, one that occurs only in forms of life that arephylogenetically more highly developed.
Pattern-recognition receptors (PRRs) come into play here. These are receptors that recognize the gross, primarily structural features of molecules not innate to the host organism. PRRs include, for example,lipids with a totally different basic chemical structure. Such receptors are bound directly to cells of the immune system and cause immediate activation of their respective nonspecific immune cells.
A prime example of such a foreign ligand is bacterialendotoxin. When endotoxin enters the bloodstream, it activates the early-phase response, which can lead toseptic shock anddisseminated intravascular coagulation.
As a membrane surface receptor, TLR2 recognizes manybacterial,fungal,viral, and certainendogenous substances. In general, this results in the uptake (internalization,phagocytosis) of bound molecules byendosomes/phagosomes and in cellular activation; thus such elements ofinnate immunity as macrophages,PMNs and dendritic cells assume functions of nonspecific immune defense, B1a and MZ B cells form the first antibodies, and specific antibody formation gets started in the process.Cytokines participating in this includetumor necrosis factor-alpha (TNF-α) and variousinterleukins (IL-1α,IL-1β,IL-6,IL-8,IL-12). Before the TLRs were known, several of the substances mentioned were classified asmodulins. Due to the cytokine pattern, which corresponds more closely toTh1, animmune deviation is seen in this direction in most experimental models, away fromTh2 characteristics.Conjugates are being developed asvaccines or are already being used without a priori knowledge.
A peculiarity first recognized in 2006 is theexpression of TLR2 on Tregs (a type of T cell), which experience bothTCR-controlledproliferation and functional inactivation. This leads to disinhibition of the earlyinflammation phase and of specific antibody formation. Following a reduction in pathogen count, many pathogen-specific Tregs are present that, now without a TLR2 signal, become active and inhibit the specific and inflammatory immune reactions (see alsoTNF-β,IL-10). Older literature that ascribes a direct immunity-stimulating effect via TLR2 to a given molecule must be interpreted in light of the fact that the TLR2 knockouts employed typically have very few Tregs.
Functionally relevantpolymorphisms are reported that cause functional impairment and thus, in general, reduced survival rates, in particular in infections/sepsis with Gram-positive bacteria.
Signal transduction is depicted underToll-like receptor.
TLR2 isexpressed onmicroglia,Schwann cells,monocytes, macrophages, dendritic cells,polymorphonuclear leukocytes (PMNs or PMLs),B cells (B1a, MZ B, B2), andT cells, includingTregs (CD4+CD25+ regulatory T cells). In some cases, it occurs in aheterodimer (combination molecule), e.g., paired withTLR-1 orTLR-6. TLR2 is also found in theepithelia ofair passages,pulmonary alveoli,renal tubules, and theBowman's capsules inrenal corpuscles. TLR2 is also expressed by intestinal epithelial cells and subsets of lamina propria mononuclear cells in the gastrointestinal tract.[10] In theskin, it is found onkeratinocytes andsebaceous glands;spc1 is induced here, allowing a bactericidalsebum to be formed.
TLR2 gene has been observed progressively downregulated inHuman papillomavirus-positiveneoplastic keratinocytes derived from uterine cervicalpreneoplastic lesions at different levels of malignancy.[11] For this reason, TLR2 is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervicalpreneoplastic lesions progression.[11]
The following ligands have been reported to beagonists of the toll-like receptor 2:
| Agonist | Organism |
|---|---|
| Lipoteichoic acid | Gram-positive bacteria |
| atypicalLPS | Leptospirosis andPorphyromonas gingivalis |
| MALP-2 and MALP-404 (lipoproteins) | Mycoplasma |
| - | Chlamydophila pneumoniae |
| OspA | Borrelia burgdorferi (Lyme disease) |
| Porin | Neisseria meningitidis,Haemophilus influenzae |
| Antigen mixtures | Cutibacterium acnes |
| LcrV | Yersinia |
| Lipomannan | Mycobacterium:Mycobacterium tuberculosis |
| GPI anchor | Trypanosoma cruzi |
| Lysophosphatidylserine | Schistosoma mansoni |
| Lipophosphoglycan (LPG) | Leishmania major |
| Glycophosphatidylinositol (GPI) | Plasmodium falciparum |
| Zymosan (abeta-glucan)[12][13] | Saccharomyces cerevisiae |
| - | Malassezia (commensal yeast) |
| Antigen mixtures | Aspergillus fumigatus,Candida albicans |
| hsp60, as peptide transporter andadjuvant for antigen presentation | - |
| Glycoprotein (gH/gL, gB)[14] | Herpes simplex virus |
| - | Varicella zoster virus |
| - | Cytomegalovirus (CMV) |
| Hemagglutinin | Measles |
| Active hexose correlated compound (AHCC)[15] | Shiitake |
TLR 2 has been shown tointeract withTLR 1[16] andTOLLIP.[17] It has been shown that TLR2 can interact with spike and E-protein of SARS-CoV-2.[18] The result of these interactions can be the activation of the immune system.[18]
TLR2 resides on the plasma membrane where it responds to lipid-containingPAMPs such as lipoteichoic acid and di- and tri-acylated cysteine-containing lipopeptides. It does this by forming dimeric complexes with eitherTLR 1 orTLR6 on the plasma membrane.[19] TLR2 interactions with malarialglycophosphatidylinositols ofPlasmodium falciparum was shown[20] and a detailed structure of TLR–GPI interactions was computationally predicted.[21]
Various single nucleotide polymorphisms (SNPs) of the TLR2 have been identified[22] and for some of them an association with faster progression and a more severe course of sepsis in critically ill patients was reported.[23] No association with occurrence of severe staphylococcal infection was found.[24] Moreover, a recent study reported rs111200466, a TLR2 promoter insertion/deletion polymorphism as a prognosis factor in HIV-1 disease progression. The authors showed a correlation of the polymorphism with a faster progression to the CD4+ < 200 cells/μL outcome for the deletion allele carriers.[25]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
