miR-142-3p Is Involved in CD25+ CD4 T Cell Proliferation by Targeting the Expression of Glycoprotein A Repetitions Predominant

J Immunol. 2013 Jun 15;190(12):6579-88. doi: 10.4049/jimmunol.1202993. Epub 2013 May 6.

Abstract

Because of the numerous targets of microRNAs (miRNAs), functional dissection of specific miRNA/mRNA interactions is important to understand the complex miRNA regulatory mechanisms. Glycoprotein A repetitions predominant (GARP) is specifically expressed on regulatory CD25(+) CD4 T cells upon their activation. GARP has a long 3' untranslated region containing five highly conserved regions suggesting miRNA regulation of its expression. Although GARP is physiologically expressed on a cell subset characterized by stringent control of proliferation, amplification of the GARP gene has been found in many tumors characterized by uncontrolled proliferation. In this study, we investigated in detail miRNA regulation of GARP expression, in particular by miR-142-3p, and dissected the functional outcome of miR-142-3p/GARP mRNA interaction. We demonstrate that miR-142-3p binds directly to the 3' untranslated region of GARP and represses GARP protein expression by Argonaute 2-associated degradation of GARP mRNA. Functionally, miR-142-3p-mediated regulation of GARP is involved in the expansion of CD25(+) CD4 T cells in response to stimulation. The data indicate that miR-142-3p regulates GARP expression on CD25(+) CD4 T cells and, as a result, their expansion in response to activation. Our data provide novel insight into the molecular mechanisms controlling regulatory T cell expansion. They may also have implications for understanding tumor cell biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • 3' Untranslated Regions / immunology
  • Animals
  • Base Sequence
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / immunology*
  • HEK293 Cells
  • Humans
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Jurkat Cells
  • Lymphocyte Activation / genetics*
  • Lymphocyte Activation / immunology
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • MicroRNAs / genetics*
  • MicroRNAs / immunology
  • Molecular Sequence Data
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • 3' Untranslated Regions
  • Interleukin-2 Receptor alpha Subunit
  • LRRC32 protein, human
  • MIRN142 microRNA, human
  • Membrane Proteins
  • MicroRNAs