title: MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells.
abstract: 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.
authors.affiliation: Division of Molecular Immunology, MRC, National Institute for Medical Research, London NW7 1AA, UK.
authors.forename: Isobel S
authors.initials: IS
authors.lastname: Okoye
authors.affiliation: Division of Molecular Immunology, MRC, National Institute for Medical Research, London NW7 1AA, UK.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Coomes
authors.affiliation: Division of Molecular Immunology, MRC, National Institute for Medical Research, London NW7 1AA, UK.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Pelly
authors.affiliation: Division of Molecular Immunology, MRC, National Institute for Medical Research, London NW7 1AA, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czieso
authors.affiliation: Division of Molecular Immunology, MRC, National Institute for Medical Research, London NW7 1AA, UK.
authors.forename: Venizelos
authors.initials: V
authors.lastname: Papayannopoulos
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Tolmachova
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
authors.affiliation: Division of Molecular Immunology, MRC, National Institute for Medical Research, London NW7 1AA, UK. Electronic address: mwilson@nimr.mrc.ac.uk.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics; D055354:Exosomes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D022761:Gene Transfer, Horizontal / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D043244:Ribonuclease III / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000075745:rab27 GTP-Binding Proteins
chemical_list: D018941:Antigens, CD19; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse; D000075745:rab27 GTP-Binding Proteins; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; C512958:Rab27b protein, mouse; C512962:Rab27a protein, mouse; D053487:DEAD-box RNA Helicases; D020691:rab GTP-Binding Proteins