microRNA-142–mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance
Nelomi Anandagoda, … , Jane K. Howard, Graham M. Lord
Nelomi Anandagoda, … , Jane K. Howard, Graham M. Lord
Published March 1, 2019; First published February 11, 2019
Citation Information: J Clin Invest. 2019;129(3):1257-1271. https://doi.org/10.1172/JCI124725.
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Categories: Research Article Autoimmunity Immunology

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

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.

Authors

Nelomi Anandagoda, Joanna C.D. Willis, Arnulf Hertweck, Luke B. Roberts, Ian Jackson, M. Refik Gökmen, Richard G. Jenner, Jane K. Howard, Graham M. Lord

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Figure 6

Pharmacological inhibition of PDE3B or genetic deletion of Pde3b reverses the lethality and phenotype of the autoimmune syndrome induced by Treg-specific loss of miR-142.

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Pharmacological inhibition of PDE3B or genetic deletion of Pde3b reverse...
(A) Weight (left) and survival (right) of TregΔ142 and WT littermate control mice after 8 weeks of treatment with 6.4 mg/kg intraperitoneal cilostamide or control (n ≥ 3 for WT mice and n ≥ 6 for TregΔ142 mice). Loss of more than 15% of body weight was the predefined mortality endpoint. (B) Coculture Treg suppression assay after 4 weeks of cilostamide treatment. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA. Data combined from 3 independent experiments. (C) Weight (left) and survival (right) of Pde3b–/– × TregΔ142, TregΔ142, Pde3b+/– × TregΔ142, and WT mice. n ≥ 5 (Pde3b–/– × TregΔ142); n ≥ 3 (Pde3b+/– × TregΔ142); n ≥ 7 (TregΔ142); and n ≥ 5 (WT mice). (D) Coculture Treg suppression assay comparing germline deletion of Pde3b (Pde3b–/– × TregΔ142) with TregΔ142 and WT littermate control mice. P values signify comparison between Pde3b–/– × TregΔ142 and TregΔ142. *P < 0.05; **P < 0.01, 1-way ANOVA. Data combined from 2 independent experiments. n ≥ 6. (E) H&E staining of formalin-fixed, paraffin-embedded sections from ear skin, liver, and lung (left) with histological scoring as described in Methods (right). Original magnification, ×20 (ear skin); ×10 (liver and lung). *P < 0.05, Student’s t test. n = 5 (Pde3b–/– × TregΔ142, TregΔ142 and WT); n = 3 (Pde3b+/– × TregΔ142). WT and TregΔ142 skin, lung, and liver histology are also shown in Figure 3D.