The Stimulator of Interferon Genes (STING) is activated by cytosolic DNA sensors such as cyclic GMP-AMP Synthase (cGAS) to induce interferon type I (IFN-I). Dendritic cells (DCs) that engulf dying tumor cells incite anti-tumor T cell immunity by sensing tumor cell DNA to activate STING/IFN-I signaling. Paradoxically, we find that DNA sensing to activate STING/IFN-I signaling induces DCs to express indoleamine 2, 3 dioxygenase (IDO), which activates regulatory T cells (Tregs). Thus treatment with DNA nanoparticles (DNPs) or cyclic dinucleotides (CDNs) to activate STING attenuated Experimental Autoimmune Encephalomyelitis (EAE), arthritis, and therapeutic responses were dependent on STING/IFN-I signaling to induce IDO. DNP and CDN treatments were also effective in slowing Type I Diabetes (T1D) progression in susceptible female Non-Obese Diabetic (NOD) mice. STING ablation also abolished IDO-dependent regulatory responses to apoptotic cells, suggesting that DNA from dying cells is sensed to activate the STING/IFN-I pathway and induce IDO to suppress autoimmunity. Moreover, cGAS and STING ablation abolished the ability of Lewis Lung carcinoma (LLC) tumor cells to induce local IDO, which suppresses anti-tumor immunity. These findings support the hypothesis that DNA from dying cells is sensed to activate STING/IFN-I in regulatory DCs that suppress T cell immunity and autoimmunity at sites of chronic inflammation associated with autoimmunity and tumor growth.

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