Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Augusta, GA 30912;
J Immunol. 2013 Oct 1;191(7):3509-13. doi: 10.4049/jimmunol.1301419. Epub 2013 Aug 28.
Cytosolic DNA sensing via the stimulator of IFN genes (STING) adaptor incites autoimmunity by inducing type I IFN (IFN-αβ). In this study, we show that DNA is also sensed via STING to suppress immunity by inducing IDO. STING gene ablation abolished IFN-αβ and IDO induction by dendritic cells (DCs) after DNA nanoparticle (DNP) treatment. Marginal zone macrophages, some DCs, and myeloid cells ingested DNPs, but CD11b(+) DCs were the only cells to express IFN-β, whereas CD11b(+) non-DCs were major IL-1β producers. STING ablation also abolished DNP-induced regulatory responses by DCs and regulatory T cells, and hallmark regulatory responses to apoptotic cells were also abrogated. Moreover, systemic cyclic diguanylate monophosphate treatment to activate STING induced selective IFN-β expression by CD11b(+) DCs and suppressed Th1 responses to immunization. Thus, previously unrecognized functional diversity among physiologic innate immune cells regarding DNA sensing via STING is pivotal in driving immune responses to DNA.
细胞质 DNA 通过干扰素基因刺激物 (STING) 衔接蛋白的感应，通过诱导 I 型干扰素 (IFN-αβ) 引发自身免疫。在这项研究中，我们表明 DNA 也可以通过 STING 感应来抑制免疫，方法是诱导 IDO。STING 基因缺失消除了 DNA 纳米颗粒 (DNP) 处理后树突状细胞 (DC) 中 IFN-αβ 和 IDO 的诱导。边缘区巨噬细胞、一些 DC 和髓样细胞摄取了 DNPs，但只有 CD11b(+) DC 表达 IFN-β，而 CD11b(+) 非-DC 是主要的 IL-1β 产生细胞。STING 缺失也消除了 DNP 诱导的 DC 和调节性 T 细胞的调节反应，凋亡细胞的标志性调节反应也被消除。此外，系统的环二鸟苷酸单磷酸治疗以激活 STING 诱导了 CD11b(+) DC 中选择性 IFN-β 的表达，并抑制了对免疫接种的 Th1 反应。因此，以前未被认识到的生理先天免疫细胞中关于通过 STING 进行 DNA 感应的功能多样性对于驱动对 DNA 的免疫反应至关重要。
