Hierarchical requirement for CpG Motifs in dendritic cell activation induced by DNA‐containing immune‐complexes

In systemic lupus erythematosus (SLE), immune complexes (ICs) containing mammalian DNA activate dendritic cells (DC) at least in part through Toll‐like receptor 9 (TLR9). However, the DNA sequence required for this TLR9 activation is unclear because, unlike bacterial or viral DNA, mammalian DNA contains very few of the classical unmethylated CpG motifs believed to be important for TLR9 activation. To address this question, we treated mouse DC with immune complexes containing DNA fragments of defined sequence, including sequences obtained from CpG islands within the mammalian genome, and measured cytokine production and co‐stimulatory molecule upregulation. We found that although the strongest activation was elicited by classical unmethylated CpG motifs, effective activation was also elicited by methylated classical CpG motifs and by unmethylated non‐classical CpG motifs. The activation was entirely TLR9‐dependent. In contrast, no activation was elicited by DNA lacking CG sequences. Overall, the data indicate that IC containing DNA sequences found in mammalian DNA are able to activate DC, providing a possible explanation for how DNA‐containing IC might cause immune system activation in patients with SLE. This research is supported by a NIH (NIAMS) program project grant.