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Not Recognizing Ourselves

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Science  13 Jan 2006:
Vol. 311, Issue 5758, pp. 149
DOI: 10.1126/science.311.5758.149c

Toll-like receptors (TLRs) recognize conserved motifs in microbial molecules, enabling them to initiate immune responses against pathogens. Whereas most TLRs are found on the cell surface, those that recognize bacterial and viral nucleic acids are inside. Barton et al. investigated the functional importance of the endosomal localization of TLR9, a TLR that is activated by DNA containing unmethylated CpG motifs, which occur frequently in bacterial and viral DNA. Immunofluorescence analysis of chimeric receptors containing the transmembrane or cytosolic domains of TLR9 or TLR4 (which is found on the plasma membrane) revealed that localization depended on the transmembrane domain. TLR9N4C, a chimeric receptor made of the TLR9 ectodomain and the TLR4 cytosolic and transmembrane domains, localized to the cell surface. Dendritic cells expressing TLR9N4C responded to CpG DNA as effectively as cells expressing TLR9 did. However, dendritic cells expressing TLR9N4C, unlike those expressing TLR9, failed to respond to herpes simplex virus; moreover, macrophages expressing TLR9N4C, but not macrophages expressing TLR9, were stimulated by exposure to extracellular mammalian DNA. Thus, the authors propose that the intracellular localization of TLR9 may be critical to prevent it seeing self DNA. — EMA

Nat. Immunol. 7, 49 (2006).

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