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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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 2

MiR-142–deficient Tregs develop normally, but fail to suppress Teff responses in vitro.

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MiR-142–deficient Tregs develop normally, but fail to suppress Teff resp...
(A) Number and proportion (%) of FOXP3+ (CD4+YFP+) cells at successive stages of thymus development (n = 4 per group). (B) Number of FOXP3+ cells in spleen (left) and peripheral lymph node (pLN) (right) samples (n = 8). (C) Flow cytometry histograms of peripheral Tregs (CD4+CD25+FOXP3+) stained for surface and intracellular Treg markers (n ≥ 4 per group). (D) Flow cytometry and cytokine secretion profiles of CD3+CD4+ and CD3+CD8+ T cells. **P < 0.01, 2-tailed Student’s t test. n ≥ 4 per group. (E) Flow cytometry and intracytoplasmic cytokine capture data for CD25 surface expression and IL-2 production in TregΔ142 (CD4+YFP+) versus WT Tregs (CD4+CD25+FOXP3+). **P < 0.01, 2-tailed Student’s t test. n = 6 per group. (F) Coculture suppression assays; P value represents comparison of WT Tregs, WT Teffs, and TregΔ142 WT Teffs (data combined from 3 independent experiments). CTV, CellTrace Violet. *P < 0.05, 2-tailed Student’s t test. n > 3 per group.