Engineering DNA Nanoparticles as Immunomodulatory Reagents that Activate Regulatory T Cells

Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine are efficient vehicles to transduce DNA into cells and organisms. DNA/polyethylenimine nanoparticles (DNPs) also elicit rapid and systemic release of proinflammatory cytokines that promote antitumor immunity. In this study, we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid upregulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFN-alpha beta) and II IFN-gamma), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-gamma receptor signaling was not essential for this response. Moreover, systemic IFN-gamma release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-alpha beta release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-alpha beta production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-gamma. DNP treatment to induce IDO and activate Tregs blocked Ag-specific T cell responses elicited in vivo following immunization and suppressed joint pathology in a model of immune-mediated arthritis. Thus, DNPs lacking TLR9 ligands may be safe and effective reagents to protect healthy tissues from immune-mediated destruction in clinical hyperimmune syndromes. The Journal of Immunology, 2012, 188: 4913-4920.