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microRNA-142-mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance

Anandagoda, N; Willis, JC; Hertweck, A; Roberts, LB; Jackson, I; Gökmen, MR; Jenner, RG; ... Lord, GM; + view all (2019) microRNA-142-mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance. Journal of Clinical Investigation 10.1172/JCI124725. (In press). Green open access

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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.

Type: Article
Title: microRNA-142-mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI124725
Publisher version: http://doi.org/10.1172/JCI124725
Language: English
Additional information: Copyright © 2019 Anandagoda et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Autoimmunity, Immunology, Molecular genetics, T cells
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10068833
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