PDF(Pubmed)
Abstract：
The Type-I interferon (IFN-I) response is the major outcome of stimulator of interferon genes (STING) activation in innate cells. STING is more abundantly expressed in adaptive T cells; nevertheless, its intrinsic function in T cells remains unclear. Intriguingly, we previously demonstrated that STING activation in T cells activates widespread IFN-independent activities, which stands in contrast to the well-known STING-mediated IFN response. Here, we have identified that STING activation induces regulatory T cells (Tregs) differentiation independently of IRF3 and IFN. Specifically, the translocation of STING from the endoplasmic reticulum to the Golgi activates mitogen-activated protein kinase (MAPK) activity, which subsequently triggers transcription factor cAMP response element-binding protein (CREB) activation. The activation of the STING-MAPK-CREB signaling pathway induces the expression of many cytokine genes, including interleukin-2 (IL-2) and transforming growth factor-beta 2 (TGF-β2), to promote the Treg differentiation. Genetic knockdown of MAPK p38 or pharmacological inhibition of MAPK p38 or CREB markedly inhibits STING-mediated Treg differentiation. Administration of the STING agonist also promotes Treg differentiation in mice. In the Trex1-/- autoimmune disease mouse model, we demonstrate that intrinsic STING activation in CD4+ T cells can drive Treg differentiation, potentially counterbalancing the autoimmunity associated with Trex1 deficiency. Thus, STING-MAPK-CREB represents an IFN-independent signaling axis of STING that may have profound effects on T cell effector function and adaptive immunity.
摘要：
I型干扰素（IFN-I）反应是先天细胞中干扰素基因刺激因子（STING）激活的主要结果。STING在适应性T细胞中更丰富地表达;然而，其在T细胞中的内在功能尚不清楚。有趣的是，我们先前证明了T细胞中的STING激活激活了广泛的IFN非依赖性活性，这与众所周知的STING介导的IFN应答相反。这里,我们已经确定STING激活诱导调节性T细胞（Tregs）分化独立于IRF3和IFN。具体来说,STING从内质网到高尔基体的易位激活丝裂原活化蛋白激酶（MAPK）活性，随后触发转录因子cAMP反应元件结合蛋白（CREB）激活。STING-MAPK-CREB信号通路的激活诱导多种细胞因子基因的表达,包括白细胞介素-2（IL-2）和转化生长因子-β2（TGF-β2），促进Treg分化。MAPKp38的遗传敲低或MAPKp38或CREB的药理学抑制显著抑制STING介导的Treg分化。STING激动剂的施用还促进小鼠中的Treg分化。在Trex1-/-自身免疫性疾病小鼠模型中，我们证明CD4+T细胞中固有的STING激活可以驱动Treg分化，可能抵消与Trex1缺乏相关的自身免疫。因此，STING-MAPK-CREB代表STING的IFN非依赖性信号轴,其可能对T细胞效应子功能和适应性免疫具有深远的影响。
