Abstract
Among the 10 human Toll-like receptors (TLRs), TLR2 appears to be unique in its requirement for cooperation with other TLRs, namely TLR1 and TLR6, to mediate cell signaling. Through reconstitution experiments, we have defined more precisely the function of these human TLRs. Human colonic epithelial cells cotransfected with TLR1 and -2 preferentially respond to a synthetic tripalmitoylated bacterial lipopeptide analogue (Pam(3)CSK(4)). However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and -2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue. Conversely, human TLR2 and -6 exclusively respond to lipopeptides possessing a diacylglycerol group. Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2. These results suggest that the chirality of the central carbon of the diacylglycerol group of these agonists is a structural determinant for human TLR recognition. Examination of chimeric receptors, generated by domain exchange between TLR1 and -6, has revealed that leucine-rich repeats 9-12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides. However, additional chimeric constructs reveal that this region alone is not sufficient to generate receptors that can functionally cooperate with TLR2. Our results support the idea that TLR1 and TLR6 diverged during evolution to differentially recognize natural lipoprotein structures and that this function has been conserved with respect to the human receptors.
Highlights
IntroductionIn contrast to other Toll-like receptors (TLRs), TLR2 appears to mediate cellular responses to a much wider variety of microbes and microbial components
SW620 Epithelial Cells Are Deficient in TLR1, -2, and -6 Expression—Toward defining a functional role for human Toll-like receptors 1, 2, and 6, we screened a variety of cell lines for endogenous expression of these receptors by RT-PCR
Following the screening of a variety of cell lines, we discovered that SW620 cells, a human epithelial carcinoma cell line, expressed no detectable TLR1 or TLR2 by RT-PCR and that TLR6 message was only barely detectable after extended PCR cycles (Fig. 1)
Summary
In contrast to other TLRs, TLR2 appears to mediate cellular responses to a much wider variety of microbes and microbial components In accord with this diverse recognition, TLR2-deficient mice exhibit differential outcomes in a vast array of infection models (reviewed in Ref. 3). Studies using peritoneal macrophages derived from TLR-deficient mice have revealed that murine TLR1 and TLR6 predominantly mediate responses to triacylated and diacylated lipopeptides, respectively [13,14,15]. With respect to TLR2, the murine receptor appears to recognize both tripalmitoylated and trilauroylated lipopeptides, whereas the human receptor only recognizes the former but not the latter compound [20] Together, these studies demonstrate that one cannot make strict inferences about specificity with respect to TLR recognition between mice and humans.
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