Expanded Human Non-Cytotoxic CD8CD45RC Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice.

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 CD8CD45RC Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8CD45RC 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 CD8CD45RC Tregs are equivalent to canonical CD4CD25CD127 Tregs for suppression of allogeneic immune responses . Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD.