Genomic variants of TLR1 – It takes (TLR‐)two to tango

Abstract

Toll-like receptors (TLR) are innate immune sensors of microbial cell wall products that initiate early host responses. The TLR2 receptor complex has been shown to contain heterodimers of TLR2 with either TLR1 or TLR6 enabling the host to detect different microbial molecules, such as lipopeptides of different chemical composition. In this issue of the European Journal of Immunology, an important role in the sensing of microbial products for I602S, a single nucleotide polymorphism (SNP) in human TLR1 has been identified. This result, in combination with another recently published report on this polymorphism elucidating a functional role in cell trafficking (surface expression of the receptor complex in individuals carrying the SNP was altered), provide genetic evidence affirming the important function of TLR1 as an essential coreceptor for TLR2. Sensing of microbial products and the immediate inflammatory response are critical for an effective host defense. Toll-like receptors (TLR) have emerged over the past ten years as essential pattern recognition receptors of the innate immune system that act by sensing foreign molecules of viral, microbial, fungal, protozoal and helminth origin. Activation of TLR induces the expression of gene products involved in direct killing of the pathogen, inflammatory processes, and the initiation of events required for adaptive immune responses. Of the ten human TLR, several are expressed within intracellular endosomes where they mediate recognition of viral and bacterial nucleic acids (TLR3, and TLR7-TLR9). All others are expressed on the cell surface including TLR4, the sensor of Gram-negative lipopolysaccharide (LPS), and TLR5, which senses bacterial flagellin. A variety of microbial and fungal components are sensed by TLR2, and it has been shown that TLR1 and TLR6 are coreceptors for TLR2 forming either TLR2/1 or TLR2/6 heterodimers with differing agonist specificities [1]. TLR1 and TLR2 cooperate to sense triacylated bacterial lipoproteins, while TLR6 and TLR2 recognize certain diacylated lipoproteins, although this theory was recently challenged and modified [2]. It has been hypothesized that by forming heterodimers, a wider variety of microbial products are sensed by the TLR2 complex and this ability is extended by additional coreceptors such as CD14 and CD36, as well as by soluble serum factors such as lipopolysaccharide binding protein (LBP) [3,4]. Eur. J. Immunol. 2007. 37: 2059-2062 In a recent study conducted by us [7], we also identified I602S as a functionally relevant SNP. This finding arose from the observation that blood-derived monocytes from certain individuals appeared to completely lack cell surface TLR1 expression. The frequency of the observation, as well as the position of I602S within the receptor, led us to investigate the role of I602S in this phenotype. Similar to Hawn et al., [6], we found that blood cells derived from individuals homozygous for 602S exhibited attenuated responses to triacylated lipopeptides [7]. We were also able to reconstitute the ph...

Toll-like Receptor 2 Signaling in CD4+ T Lymphocytes Promotes T Helper 17 Responses and Regulates the Pathogenesis of Autoimmune Disease

“…To further investigate TLR expression in T cell subsets, we performed real-time RT-PCR on Th1, Th2, and Th17 subsets using bone marrow-derived macrophages and RFP + γδ T cells from IL-17F-RFP reporter mice as positive controls. It has previously been shown that TLR2 signaling requires heterodimerization with TLR1 or TLR6 (Schumann and Tapping, 2007). In accordance, TLR1, 2, and 6 mRNAs were expressed to the highest degree in Th17 cells compared to Th1 and Th2 subsets (Figure 1A and Figure S1A available online).…”

The Oxidative Stress Product Carboxyethylpyrrole Potentiates TLR2/TLR1 Inflammatory Signaling in Macrophages

“…TLR2, unlike the other TLRs, functions as a heterodimer forming either a TLR2/TRL1 or TLR2/TLR6 complex, allowing TLR2 to discriminate between different types of ligands [29], [30]. TLR2/TLR1 heterodimers bind triacylated lipoproteins (e.g., Pam3CSK4 and lipomannan [LM]) while TLR2/TLR6 heterodimers bind diacylated lipoproteins (Pam2CSK4, lipoteichoic acid [LTA]) [31]–[33]. We tested if CEP potentiated signaling from either TLR2/TLR1, TLR2/TLR6, or both by co-stimulating BMDMs with CEP-BSA and either Pam3CSK4, LM, Pam2CSK4, or LTA.…”

A TIR Domain Variant of MyD88 Adapter-like (Mal)/TIRAP Results in Loss of MyD88 Binding and Reduced TLR2/TLR4 Signaling

“…Some of these changes may be caused by the presence of a SNP in the coding region of the protein. The effects of SNPs on the structure of proteins and the consequent effect on TLR signaling have been described in many studies (32)(33)(34)(35).…”