Abstract
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.
Highlights
Introduction miRNAs are a class of small (~21–25 nucleotides), highly conserved, endogenous noncoding RNAs that regulate gene expression posttranscriptionally. This function is mediated through binding of the miRNA-containing RNA-induced silencing complex to complementary sequences in the 3′ UTR of target mRNAs, causing mRNA degradation or translational inhibition [1, 2]
The Treg lineage is defined by expression of the transcription factor forkhead box P3 (FOXP3, known as Scurfin), whose gene locus is located on the X chromosome [7]
We show that miR-142-5p directly targets phos- FoxP3YFP–Cre model allowed for deletion of a target gene in Tregs phodiesterase-3b (Pde3b) mRNA, limiting PDE3B protein levels only, as previously described [27]
Summary
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. 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. 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
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