Journal
FRONTIERS IN IMMUNOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2017.02014
Keywords
transplantation; tolerance; Treg; cell therapy; graft; GVHD; NSG mice
Categories
Funding
- Fondation Progreffe
- Labex IGO program - National Research Agency [ANR-11-LABX-0016-01]
- French Government [ANR-10-IBHU-005]
- Nantes Metropole
- Pays de la Loire Region
- ESOT
- ROTRF
- Labex IGO
- Progreffe
- Fondation pour la Recherche Medicale
- FINOX Biotech FORWARD initiative
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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(+) CD45RC(low/-) Tregs expressing Foxp3 and producing IFN gamma, IL-10, IL-34, and TGF beta to mediate their suppressive activity. We demonstrate that total CD8+ CD45RC(low/-) 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(+) CD45RC(low/-)bTregs are equivalent to canonical CD4(+) CD25(high)CD127(low/-) 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.
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