Sci. STKE, 26 April 2005
IMMUNOLOGY Spatial Restriction of Toll-Like Receptor Signals
Signals that cause production of type-1 interferon (IFN-α/β) constitute an important part of the mammalian immune response to microbial infection. Why this response is generated by plasmacytoid dendritic cells (pDCs) but not by other cells--even conventional dendritic cells--has been unclear. Microbial products are detected by the receptor TLR9 (Toll-like receptor 9), which activates a transcription factor complex that contains the transcription factor IRF-7 (interferon regulatory factor-7) and the adaptor protein MyD88. Honda et al. monitored localization of fluorescently tagged oligodeoxynucleotide ligands of TLR9 and found that a ligand that strongly activated IFN production, CpG-A, was localized in endosomes in cultured primary mouse pDCs, whereas a less effective ligand, CpG-B, appeared to be localized to lysosomes. MyD88 and IRF-7 were also localized in endosomes in cells exposed to CpG-A. In conventional DCs (cDCs), both ligands were associated with lysosomes and failed to strongly stimulate IFN production. However, if CpG-A was modified by formation of a complex with the cationic lipid 1,2-dioleoyloxy-3-trimethylammonium-propane (DOTAP), which caused it to be localized in endosomes of cDCs, IFN production was enhanced. It is not known exactly how TLR-9-bound CpG ODNs are retained in endosomes and how this is coordinated with release of the Myd88-IRF-7 complex to the nucleus, where it enhances IFN gene transcription. The authors note that more detailed study of signaling from endosomal vesicles and their trafficking may help explain how distinct forms of unmethylated DNA can specifically alter gene expression by modulating spatial restriction of signaling components.
K. Honda, Y. Ohba, H. Yanai, H. Negishi, T. Mizutani, A. Takaoka, C. Taya, T. Taniguchi, Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035-1040 (2005). [PubMed]
Citation: Spatial Restriction of Toll-Like Receptor Signals. Sci. STKE 2005, tw152 (2005).
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