The Immunostimulatory Activity of Unmethylated and Methylated CpG Oligodeoxynucleotide Is Dependent on Their Ability To Colocalize with TLR9 in Late Endosomes
- 1 June 2010
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 184 (11), 6092-6102
- https://doi.org/10.4049/jimmunol.0802442
Abstract
TLR9 recognizes CpG motifs present in pathogenic DNA and triggers potent immune responses. It is generally accepted that TLR9 distinguishes pathogenic DNA based, in part, on methylation status, where TLR9 binds unmethylated but not methylated CpG. However, we showed that methylated CpG induces potent TLR9-mediated responses when delivered in lipid nanoparticles. In this article, we report that methylation dictates the ability of free CpG DNA to colocalize with TLR9 in late endosomes. However, when delivered in lipid nanoparticles, CpG DNA and TLR9 colocalize, regardless of methylation status. Therefore, it is proposed that the ability of immune cells to distinguish unmethylated pathogenic from methylated mammalian DNA is controlled by a mechanism that regulates TLR9 mobilization and colocalization rather than a differential binding affinity.Keywords
This publication has 26 references indexed in Scilit:
- Toll-like receptor function and signalingJournal of Allergy and Clinical Immunology, 2006
- CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretionThe Journal of cell biology, 2006
- Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNANature Immunology, 2005
- Bovine natural killer cells acquire cytotoxic/effector activity following activation with IL-12/15 and reduce Mycobacterium bovis BCG in infected macrophagesJournal of Leukocyte Biology, 2005
- Macrophage activation by a DNA/cationic liposome complex requires endosomal acidification and TLR9-dependent and -independent pathwaysJournal of Leukocyte Biology, 2004
- Toll‐like receptor 9 binds single‐stranded CpG‐DNA in a sequence‐ and pH‐dependent mannerEuropean Journal of Immunology, 2004
- TLR9 signals after translocating from the ER to CpG DNA in the lysosomeNature Immunology, 2004
- Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartmentsEuropean Journal of Immunology, 2002
- CpG motifs in bacterial DNA trigger direct B-cell activationNature, 1995
- A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATIONCanadian Journal of Biochemistry and Physiology, 1959