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


ABSTRACT: 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 IFN?, IL-10, IL-34, and TGF? 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.

SUBMITTER: Bezie S 

PROVIDER: S-EPMC5797797 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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<i>Ex Vivo</i> Expanded Human Non-Cytotoxic CD8<sup>+</sup>CD45RC<sup>low/-</sup> Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice.

Bézie Séverine S   Meistermann Dimitri D   Boucault Laetitia L   Kilens Stéphanie S   Zoppi Johanna J   Autrusseau Elodie E   Donnart Audrey A   Nerrière-Daguin Véronique V   Bellier-Waast Frédérique F   Charpentier Eric E   Duteille Franck F   David Laurent L   Anegon Ignacio I   Guillonneau Carole C  

Frontiers in immunology 20180131


Both CD4<sup>+</sup> and CD8<sup>+</sup> Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8<sup>+</sup> Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8<sup>+</sup>CD45RC<sup>low/-</sup> Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8<sup>+</sup>CD45RC<s  ...[more]

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