Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells

Lei Huang, Henrique P. Lemos, Ngqian Li, MingHui Li, Phillip R. Chandler, Babak Baban, Tracy L. McGaha, Buvana Ravishankar, Jeffrey R. Lee, David H. Munn, Andrew L. Mellor

Research output: Contribution to journalArticle

41 Citations (Scopus)

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. IDOmediated 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.

Original languageEnglish (US)
Pages (from-to)4913-4920
Number of pages8
JournalJournal of Immunology
Volume188
Issue number10
DOIs
StatePublished - May 15 2012

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Regulatory T-Lymphocytes
Polyethyleneimine
Nanoparticles
DNA
Ligands
Poisons
Lymphoid Tissue
Natural Killer Cells
Dendritic Cells
Arthritis
Immunity
Immunization
Polymers
Up-Regulation
Therapeutics
Joints
Pathology
Cytokines
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. / Huang, Lei; Lemos, Henrique P.; Li, Ngqian; Li, MingHui; Chandler, Phillip R.; Baban, Babak; McGaha, Tracy L.; Ravishankar, Buvana; Lee, Jeffrey R.; Munn, David H.; Mellor, Andrew L.

In: Journal of Immunology, Vol. 188, No. 10, 15.05.2012, p. 4913-4920.

Research output: Contribution to journalArticle

Huang, L, Lemos, HP, Li, N, Li, M, Chandler, PR, Baban, B, McGaha, TL, Ravishankar, B, Lee, JR, Munn, DH & Mellor, AL 2012, 'Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells', Journal of Immunology, vol. 188, no. 10, pp. 4913-4920. https://doi.org/10.4049/jimmunol.1103668
Huang, Lei ; Lemos, Henrique P. ; Li, Ngqian ; Li, MingHui ; Chandler, Phillip R. ; Baban, Babak ; McGaha, Tracy L. ; Ravishankar, Buvana ; Lee, Jeffrey R. ; Munn, David H. ; Mellor, Andrew L. / Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. In: Journal of Immunology. 2012 ; Vol. 188, No. 10. pp. 4913-4920.
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