Engineering DNA nanoparticles as immunomodulatory reagents (P1076)

Abstract Cytoplasmic DNA sensing triggers anti-microbial immunity by inducing interferon type I (IFNαβ) via STING-TBK1 activation but sustained STING activation incites autoimmunity. Systemic DNA nanoparticle (DNP) treatment triggered rapid and potent tolerogenic responses in mice via selective activation of the STING-IFNαβ pathway in myeloid dendritic cells (DCs) to induce indoleamine 2, 3 dioxygenase (IDO) activity. DNPs associated rapidly with splenic marginal zone (MZ) macrophages (MΦs) and some DCs, and IFNαβ and IL-1β were induced soon after DNP injection. IFNβ1 was primarily induced in myeloid (CD11b+) DCs and this response was STING dependent, while IL-1β was induced primarily in granulocytes and was STING independent. IFNαβ-mediated IDO induction caused DCs and regulatory T cells (Tregs) to acquire potent tolerogenic phenotypes. Physiologic depletion of (CD11c+) DCs and STING ablation abolished IDO induction and tolerogenic responses to DNPs, but MZ (CD169+) MΦ depletion did not. Moreover, systemic treatment with the cyclic dinucleotide (c-diGMP) to activate STING directly induced IDO and suppressed antigen-specific Th1 responses. Thus myeloid DCs sense circulating cargo DNA and c-diGMP to induce selective IFNαβ release that promotes dominant tolerogenic responses via IDO. Targeting this distinctive tolerogenic pathway may be an effective strategy to suppress hyper-immune syndromes, including autoimmune diseases incited by excessive IFNαβ release.