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Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/-Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

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Bézie, Séverine | Meistermann, Dimitri | Boucault, Laetitia | Kilens, Stéphanie | Zoppi, Johanna | Autrusseau, Elodie | Donnart, Audrey | Nerrière-Daguin, Véronique | Bellier-Waast, Frédérique | Charpentier, Eric | Duteille, Franck | David, Laurent | Anegon, Ignacio | Guillonneau, Carole

Edité par CCSD ; Frontiers -

International audience. 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 responsesin vitro. Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD.

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