microRNA-142–mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance. Mus musculus

Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage–determining transcription factor forkhead box P3 (FOXP3), and Treg-specific deletion of miR-142 in mice (TregΔ142) resulted in spontaneous, lethal, multisystem autoimmunity, despite preserved numbers of phenotypically normal Tregs. Pharmacological inhibition and genetic ablation of PDE3B prevented autoimmune disease and reversed the impaired suppressive function of Tregs in TregΔ142 animals. These findings reveal a critical molecular switch, specifying Treg function through the modulation of a highly conserved, cell-intrinsic metabolic pathway. Modulation of this pathway has direct relevance to the pathogenesis and treatment of autoimmunity and cancer. Overall design: ChIP-seq to identify Foxp3 binding sites in murine Treg cells调节性T细胞（Tregs）通过调控自身反应性效应T细胞（Teffs）在免疫耐受中发挥核心作用。该功能依赖于细胞内高浓度环腺苷酸（cAMP）的维持。多种微小RNA（microRNAs）参与调节性T细胞的稳态维持。本研究证实，外周免疫耐受关键依赖于微小RNA-142-5p（miR-142-5p）对环腺苷酸水解酶磷酸二酯酶3b（Pde3b）的转录后抑制作用。借此，miR-142-5p作为细胞内环腺苷酸的免疫代谢调控因子，调控调节性T细胞的抑制功能。Mir142与由调节性T细胞谱系决定性转录因子叉头框P3（FOXP3）结合的超级增强子存在关联；在小鼠体内特异性敲除调节性T细胞中的miR-142（TregΔ142）后，即便表型正常的调节性T细胞数量未发生改变，仍会引发自发性、致命性多系统自身免疫病。对PDE3B进行药物抑制与基因敲除，可阻止TregΔ142小鼠发生自身免疫病，并逆转其调节性T细胞受损的抑制功能。上述研究发现揭示了一种关键的分子开关，其通过调控高度保守的细胞内在代谢通路来决定调节性T细胞的功能。对该通路的调控与自身免疫病及癌症的发病机制和治疗直接相关。总体实验设计：采用染色质免疫沉淀测序（ChIP-seq）鉴定小鼠调节性T细胞内的Foxp3结合位点。