1. Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation.
- Author
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Warth SC, Hoefig KP, Hiekel A, Schallenberg S, Jovanovic K, Klein L, Kretschmer K, Ansel KM, and Heissmeyer V
- Subjects
- 3' Untranslated Regions, Animals, Base Sequence, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes physiology, Cell Differentiation genetics, Cells, Cultured, DEAD-box RNA Helicases genetics, DEAD-box RNA Helicases metabolism, Gene Expression Regulation drug effects, Gene Regulatory Networks, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Ribonuclease III genetics, Ribonuclease III metabolism, T-Lymphocytes, Regulatory drug effects, TOR Serine-Threonine Kinases metabolism, Tretinoin pharmacology, MicroRNAs genetics, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory physiology, TOR Serine-Threonine Kinases genetics
- Abstract
Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4(+) T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T-cell-expressed miRNAs in naive mouse CD4(+) T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR-100, miR-99a and miR-10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR-99a cooperated with miR-150 to repress the expression of the Th17-promoting factor mTOR. The comparably low expression of miR-99a was strongly increased by the Treg cell inducer "retinoic acid", and the abundantly expressed miR-150 could only repress Mtor in the presence of miR-99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs., (© 2015 The Authors.)
- Published
- 2015
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