MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells

Immunity. 2014 Jul 17;41(1):89-103. doi: 10.1016/j.immuni.2014.05.019.


Foxp3(+) T regulatory (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely. Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of intercellular regulation. Here, we demonstrate that non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T-cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg-cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg-cell-mediated suppression mediated by miRNA-containing exosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / immunology
  • B-Lymphocytes / immunology
  • Cell Proliferation
  • Cytokines / metabolism
  • DEAD-box RNA Helicases / genetics
  • Exosomes / genetics*
  • Exosomes / immunology
  • Exosomes / metabolism
  • Female
  • Forkhead Transcription Factors / immunology
  • Gene Transfer, Horizontal / genetics
  • Inflammation / immunology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • RNA Interference
  • Ribonuclease III / genetics
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology
  • rab GTP-Binding Proteins / genetics
  • rab27 GTP-Binding Proteins


  • Antigens, CD19
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • MicroRNAs
  • mirnlet7 microRNA, mouse
  • rab27 GTP-Binding Proteins
  • Dicer1 protein, mouse
  • Ribonuclease III
  • Rab27b protein, mouse
  • Rab27a protein, mouse
  • DEAD-box RNA Helicases
  • rab GTP-Binding Proteins