Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival

We have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave rise in-vitro to a unique population of CD4 + CD25 − regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell response in-vitro , without needing cell-to-cell c...

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Bibliographic Details
Published in:Scientific reports 2017-09, Vol.7 (1), p.11518-19, Article 11518
Main Authors: Aiello, Sistiana, Rocchetta, Federica, Longaretti, Lorena, Faravelli, Silvia, Todeschini, Marta, Cassis, Linda, Pezzuto, Francesca, Tomasoni, Susanna, Azzollini, Nadia, Mister, Marilena, Mele, Caterina, Conti, Sara, Breno, Matteo, Remuzzi, Giuseppe, Noris, Marina, Benigni, Ariela
Format: Article
Language:English
Subjects:
631/250/1619
631/250/1854
Apoptosis
CD25 antigen
CD4 antigen
Cell cycle
Cell proliferation
Exosomes
Extracellular vesicles
Gene transfer
Humanities and Social Sciences
IKK2 protein
Immune system
Immunoregulation
Immunosuppressive agents
Kidney transplantation
Kidneys
Lymphocytes T
multidisciplinary
Nitric-oxide synthase
Science
Science (multidisciplinary)
Transplantation
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Summary:We have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave rise in-vitro to a unique population of CD4 + CD25 − regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell response in-vitro , without needing cell-to-cell contact, and induced kidney allograft survival prolongation in-vivo . Deep insight into the mechanisms behind dnIKK2-Treg-induced suppression of Tcell proliferation remained elusive. Here we document that dnIKK2-Treg release extracellular vesicles (EV) riched in exosomes, fully accounting for the cell-contact independent immunosuppressive activity of parent cells. DnIKK2-Treg-EV contain a unique molecular cargo of specific miRNAs and iNOS, which, once delivered into target cells, blocked cell cycle progression and induced apoptosis. DnIKK2-Treg-EV-exposed T cells were in turn converted into regulatory cells. Notably, when administered in-vivo , dnIKK2-Treg-EV prolonged kidney allograft survival. DnIKK2-Treg-derived EV could be a tool for manipulating the immune system and for discovering novel potential immunosuppressive molecules in the context of allotransplantation.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-08617-3