期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 3, 页码 1257-1271出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI124725
关键词
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资金
- Wellcome Trust Clinical Research Training Fellowship [107387/Z/15/Z]
- Medical Research Council (MRC) Clinical Research Training Fellowship [G1002014]
- British Heart Foundation Award [PG/12/36/29444]
- MRC [MR/R001413/1]
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' National Health Service (NHS) Foundation Trust and King's College London
- Department of Health via the NIHR comprehensive Biomedical Research Centre
- King's College London
- King's College Hospital NHS Foundation Trust
- BBSRC [BB/L010356/1, BB/L009277/1] Funding Source: UKRI
- MRC [MR/R001413/1, G0802068, MR/N006445/1, G1002014] Funding Source: UKRI
- Wellcome Trust [107387/Z/15/Z] Funding Source: Wellcome Trust
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 (Treg(Delta 142)) 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 Treg(Delta 142) 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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