Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells.
Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells.
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DOI：
10.4049/jimmunol.1103668
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发表时间：
2012-05-15
期刊：
影响因子：
--
通讯作者：
Mellor AL
中科院分区：
文献类型：
--
作者：
Huang L;Lemos HP;Li L;Li M;Chandler PR;Baban B;McGaha TL;Ravishankar B;Lee JR;Munn DH;Mellor AL
Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine (PEI)2 are efficient vehicles to transduce DNA into cells and organisms. DNA/PEI nanoparticles (DNPs) also elicit rapid and systemic release of pro-inflammatory cytokines that promote anti-tumor immunity. Here we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid up-regulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells (DCs) and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFNαβ) and II (IFNγ), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, while IFNγ receptor signaling was not essential for this response. Moreover, systemic IFNγ release was caused by TLR9-dependent activation of Natural Killer cells, while TLR9 signaling was not required for IFNαβ release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFNαβ production, induced IDO and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFNγ. DNP treatment to induce IDO and activate Tregs blocked antigen-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 hyper-immune syndromes.
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