The Role of TLR2 in Infection and Immunity

Abstract

Toll-like receptors (TLRs) are recognition molecules for multiple pathogens, including bacteria, viruses, fungi, and parasites. TLR2 forms heterodimers with TLR1 and TLR6, which is the initial step in a cascade of events leading to significant innate immune responses, development of adaptive immunity to pathogens and protection from immune sequelae related to infection with these pathogens. This review will discuss the current status of TLR2 mediated immune responses by recognition of pathogen-associated molecular patterns (PAMPS) on these organisms. We will emphasize both canonical and non-canonical responses to TLR2 ligands with emphasis on whether the inflammation induced by these responses contributes to the disease state or to protection from diseases.

Keywords: TLR1; TLR2; TLR2 ligands; TLR6; co-receptors; polymorphisms.

Figure 1

TLR2 signaling. After ligand recognition and consequent TLR2 dimer rearrangement, the TIR domain of TIRAP binds the TIR domain of TLR2 and recruits the adaptor protein MyD88. IRAKs are then recruited and IRAK 4 phosphorylates (P) IRAK1, which then initiates auto-phosphorylation. Phosphorylated IRAK1 dissociates from the complex and activates TRAF6. Since IRAK1 is rapidly degraded, IRAK2 also activates TRAF 6 in latter responses. Ubiquitinated (U) TRAF6 triggers the activation sequence TAB2 – TAK1 – IKK complex. IκB phosphorylation and ubiquitination by the IKK complex leads to its degradation and release of NF-κB translocation to the nucleus for gene up-regulation. TAK1 also activates MKK6 for subsequent JNK and p38 activation, leading to AP-1 activation that triggers gene transcription of cytokines and accessory molecules. Internalized receptor complex triggered by a viral ligand can activate by an unknown pathway IRF7/3 to IFN-β gene up-regulation or IRF2/IRF1/STAT1 for IFN-α gene up-regulation (Underhill et al., ; Watters et al., ; Liljeroos et al., ; Barbalat et al., ; Dietrich et al., ; Dunne et al., 2010). MyD88, myeloid differentiation primary-response gene 88; TIRAP, TIR adaptor protein; IRAK, interleukin-1 receptor associated kinase; TRAF, TNF receptor associated factor; TAK, transforming growth factor beta-activated kinase 1; TAB, TAK1-binding protein; MKK/JNK/P38, MAP kinases, NEMO/IKKs, kinase complex; NF-κB, nuclear factor-κB; IκB, kinase complex; AP, activator protein; IRF, interferon regulatory factor, STAT, signal transducer and activator of transcription 1.