Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation

  • Warth S
  • Hoefig K
  • Hiekel A
 et al. 
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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.

Author-supplied keywords

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • CD4-Positive T-Lymphocytes/cytology/physiology
  • Cell Differentiation/genetics
  • Cells, Cultured
  • DEAD-box RNA Helicases/genetics/metabolism
  • Gene Expression Regulation/drug effects
  • Gene Regulatory Networks
  • Green Fluorescent Proteins/genetics/metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs/*genetics
  • Molecular Sequence Data
  • Ribonuclease III/genetics/metabolism
  • T-Lymphocytes, Regulatory/*cytology/drug effects/*
  • T-cell differentiation
  • TOR Serine-Threonine Kinases/*genetics/metabolism
  • Treg cells
  • Tretinoin/pharmacology
  • miRNA function

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Authors

  • S C Warth

  • K P Hoefig

  • A Hiekel

  • S Schallenberg

  • K Jovanovic

  • L Klein

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