Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/− Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice
oleh: Séverine Bézie, Séverine Bézie, Séverine Bézie, Dimitri Meistermann, Dimitri Meistermann, Dimitri Meistermann, Laetitia Boucault, Laetitia Boucault, Laetitia Boucault, Stéphanie Kilens, Stéphanie Kilens, Johanna Zoppi, Johanna Zoppi, Elodie Autrusseau, Elodie Autrusseau, Elodie Autrusseau, Audrey Donnart, Véronique Nerrière-Daguin, Véronique Nerrière-Daguin, Véronique Nerrière-Daguin, Frédérique Bellier-Waast, Eric Charpentier, Franck Duteille, Laurent David, Laurent David, Laurent David, Ignacio Anegon, Ignacio Anegon, Ignacio Anegon, Carole Guillonneau, Carole Guillonneau, Carole Guillonneau
| Format: | Article |
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| Diterbitkan: | Frontiers Media S.A. 2018-01-01 |
Deskripsi
Both CD4+ and CD8+ Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8+CD45RClow/− Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8+CD45RClow/− Tregs can be efficiently expanded in the presence of anti-CD3/28 mAbs, high-dose IL-2 and IL-15 and that such expanded Tregs efficiently delay GVHD and human skin transplantation rejection in immune humanized mice. Robustly expanded CD8+ Tregs displayed a specific gene signature, upregulated cytokines and expansion in the presence of rapamycin greatly improved proliferation and suppression. We show that CD8+CD45RClow/− Tregs are equivalent to canonical CD4+CD25highCD127low/− Tregs for suppression of allogeneic immune responses in vitro. Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD.