Downregulation of inflammatory microRNAs by Ig-like transcript 3 is essential for the differentiation of human CD8(+) T suppressor cells

J Immunol. 2012 Apr 1;188(7):3042-52. doi: 10.4049/jimmunol.1102899. Epub 2012 Mar 2.


We have investigated the mechanism underlying the immunoregulatory function of membrane Ig-like transcript 3 (ILT3) and soluble ILT3Fc. microRNA (miRNA) expression profile identified genes that were downregulated in ILT3-induced human CD8(+) T suppressor cells (Ts) while upregulated in T cells primed in the absence of ILT3. We found that miR-21, miR-30b, and miR-155 target the 3'-untranslated region of genes whose expression was strongly increased in ILT3Fc-induced Ts, such as dual specificity phosphatase 10, B cell CLL/lymphoma 6, and suppressor of cytokine signaling 1, respectively. Transfection of miRNA mimics or inhibitors and site-specific mutagenesis of their 3'-untranslated region binding sites indicated that B cell CLL/lymphoma 6, dual specificity phosphatase 10, and suppressor of cytokine signaling 1 are direct targets of miR-30b, miR-21, and miR-155. Primed CD8(+) T cells transfected with miR-21&30b, miR-21&155, or miR-21&30b&155 inhibitors displayed suppressor activity when added to autologous CD3-triggered CD4 T cells. Luciferase reporter assays of miR-21 and miR-155 indicated that their transcription is highly dependent on AP-1. Analysis of activated T cells showed that ILT3Fc inhibited the translocation to the nucleus of the AP-1 subunits, FOSB and c-FOS, and the phosphorylation of ZAP70 and phospholipase C-γ 1. In conclusion, ILT3Fc inhibits T cell activation and induces the generation of Ts targeting multiple inflammatory miRNA pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Active Transport, Cell Nucleus
  • Binding Sites / genetics
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Down-Regulation
  • Gene Expression Regulation / immunology
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Lymphocyte Activation
  • Membrane Glycoproteins
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Subunits
  • Proto-Oncogene Proteins c-bcl-6
  • RNA, Small Interfering / pharmacology
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Receptors, Immunologic
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • Transfection


  • 3' Untranslated Regions
  • BCL6 protein, human
  • DNA-Binding Proteins
  • LILRB4 protein, human
  • Membrane Glycoproteins
  • MicroRNAs
  • Protein Subunits
  • Proto-Oncogene Proteins c-bcl-6
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Recombinant Fusion Proteins