TLR2

Toll-like receptor 2 also known as TLR2 is a is_associated_with::protein that in humans is encoded by the TLR2 is_associated_with::gene. TLR2 has also been designated as CD282 (is_associated_with::cluster of differentiation 282). TLR2 is one of the is_associated_with::toll-like receptors and plays a role in the is_associated_with::immune system. TLR2 is a is_associated_with::membrane 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.

Function
The protein encoded by this gene is a member of the is_associated_with::Toll-like receptor (TLR) family, which plays a fundamental role in is_associated_with::pathogen recognition and activation of is_associated_with::innate immunity. TLRs are highly conserved from is_associated_with::Drosophila 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 of is_associated_with::cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is expressed most abundantly in peripheral blood is_associated_with::leukocytes, and mediates host response to is_associated_with::Gram-positive bacteria and is_associated_with::yeast via stimulation of is_associated_with::NF-κB.

In the intestine, TLR2 regulates the expression of is_associated_with::CYP1A1, which is a key enzyme in detoxication of carcinogenic is_associated_with::polycyclic aromatic hydrocarbons such as is_associated_with::benzo(a)pyrene.

Background
The immune system recognizes foreign is_associated_with::pathogens and eliminates them. This occurs in several phases. In the early inflammation phase, the pathogens are recognized by antibodies that are already present (innate or acquired through prior infection; see also is_associated_with::cross-reactivity). Immune-system components (e.g. complement) are bound to the antibodies and kept near, in reserve to disable them via is_associated_with::phagocytosis by scavenger cells (e.g. is_associated_with::macrophages). is_associated_with::Dendritic cells are likewise capable of phagocytizing but do not do it for the purpose of direct pathogen elimination. Rather, they infiltrate the is_associated_with::spleen and is_associated_with::lymph nodes, and each presents components of an is_associated_with::antigen 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 are phylogenetically more highly developed.

What are called pattern-recognition receptors come into play here. This refers to receptors that recognize the gross, primarily structural features of molecules not innate to the host organism. These include, for example, is_associated_with::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 bacterial is_associated_with::endotoxin, whose effects have been known for generations. When it enters the bloodstream it causes systematic activation of the early-phase response, with all the side effects of is_associated_with::septic shock. This is known in the laboratory as the is_associated_with::Shwartzman phenomenon. The intended effect is to mobilize the organism for combat, so to speak, and eliminate most of the pathogens.

Mechanism
As a membrane surface receptor, TLR2 recognizes many is_associated_with::bacterial, fungal, viral, and certain endogenous substances. In general, this results in the uptake (internalization, is_associated_with::phagocytosis) of bound molecules by is_associated_with::endosomes/is_associated_with::phagosomes and in cellular activation; thus such elements of is_associated_with::innate 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. is_associated_with::Cytokines participating in this include is_associated_with::tumor necrosis factor-alpha (TNF-α) and various is_associated_with::interleukins (IL-1α, IL-1β, IL-6, IL-8, IL-12). Before the TLRs were known, several of the substances mentioned were classified as is_associated_with::modulins. Due to the cytokine pattern, which corresponds more closely to Th1, an is_associated_with::immune deviation is seen in this direction in most experimental models, away from Th2 characteristics. Conjugates are being developed as is_associated_with::vaccines or are already being used without a priori knowledge.

A peculiarity first recognized in 2006 is the expression of TLR2 on Tregs (a type of T cell), which experience both TCR-controlled proliferation and functional inactivation. This leads to disinhibition of the early is_associated_with::inflammation 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 also TNF-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 relevant polymorphisms are reported that cause functional impairment and thus, in general, reduced survival rates, in particular in infections/sepsis with Gram-positive bacteria.

is_associated_with::Signal transduction is depicted under is_associated_with::Toll-like receptor.

Expression
TLR2 is expressed on is_associated_with::microglia, is_associated_with::Schwann cells, is_associated_with::monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes (PMNs or PMLs), is_associated_with::B cells (B1a, MZ B, B2), and is_associated_with::T cells, including is_associated_with::Tregs (CD4+CD25+ regulatory T cells). In some cases, it occurs in a is_associated_with::heterodimer (combination molecule), e.g., paired with TLR-1 or TLR-6. TLR2 is also found in the epithelia of air passages, pulmonary alveoli, is_associated_with::renal tubules, and the is_associated_with::Bowman's capsules in is_associated_with::renal corpuscles. In the is_associated_with::skin, it is found on is_associated_with::keratinocytes and is_associated_with::sebaceous glands; spc1 is induced here, allowing a bactericidal is_associated_with::sebum to be formed.

Agonists
The following ligands have been reported to be is_associated_with::agonists of the toll-like receptor 2:

Protein-Protein Interactions
TLR 2 has been shown to interact with is_associated_with::TLR 1 and is_associated_with::TOLLIP.

Protein-Ligand Interactions
TLR2 resides on the plasma membrane where it responds to lipid-containing PAMPs such as lipoteichoic acid and di- and tri-acylated cysteine-containing lipopeptides. It does this by forming dimeric complexes with either is_associated_with::TLR 1 or is_associated_with::TLR6 on the plasma membrane. TLR2 interactions with malarial is_associated_with::Glycophosphatidylinositols of is_associated_with::Plasmodium falciparum was shown and a detailed structure of TLR–GPI interactions was computationally predicted.

Gene polymorphisms
Various single nucleotide polymorphisms (SNPs) of the TLR2 have been identified and for some of them an association with faster progression and a more severe course of sepsis in critically ill patients was reported. No association with occurrence of severe staphylococcal infection was found