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Engineering DNA Nanoparticles as Immunomodulatory Reagents that Activate Regulatory T Cells

Lookup NU author(s): Dr Lei Huang, Dr Henrique De Paula Lemos, Professor Andrew Mellor

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Abstract

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-αβ) and II (IFN-γ), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-γ receptor signaling was not essential for this response. Moreover, systemic IFN-γ release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-αβ release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-αβ production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-γ. 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.


Publication metadata

Author(s): Huang L, Lemos H, Li L, Li M, Chandler PR, Baban B, McGaha TL, Ravishankar B, Lee J, Munn DH, Mellor AL

Publication type: Article

Publication status: Published

Journal: The Journal of Immunology

Year: 2012

Volume: 188

Issue: 10

Pages: 4913-4920

Print publication date: 15/05/2012

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: http://doi.org/10.4049/jimmunol.1103668

DOI: 10.4049/jimmunol.1103668

PubMed id: 22516958


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