Donor-specific CD8+ Foxp3+ T cells protect skin allografts and facilitate induction of conventional CD4+ Foxp3+ regulatory T cells.

CD4(+) regulatory T cells play a critical role in tolerance induction in transplantation. CD8(+) suppressor T cells have also been shown to control alloimmune responses in preclinical and clinical models. However, the exact nature of the CD8(+) suppressor T cells, their induction and mechanism of function in allogeneic transplantation remain elusive. In this study, we show that functionally suppressive, alloantigen-specific CD8(+) Foxp3(+) T cells can be induced and significantly expanded by stimulating naïve CD8(+) T cells with donor dendritic cells in the presence of IL-2, TGF-β1 and retinoic acid. These CD8(+) Foxp3(+) T cells express enhanced levels of CTLA-4, CCR4 and CD103, inhibit the up-regulation of costimulatory molecules on dendritic cells, and suppress CD4 and CD8 T cell proliferation and cytokine production in a donor-specific and contact-dependent manner. Importantly, upon adoptive transfer, the induced CD8(+) Foxp3(+) T cells protect full MHC-mismatched skin allografts. In vivo, the CD8(+) Foxp3(+) T cells preferentially traffic to the graft draining lymph node where they induce conventional CD4(+) Foxp3(+) T cells and concurrently suppress effector T cell expansion. We conclude that donor-specific CD8(+) Foxp3(+) suppressor T cells can be induced and exploited as an effective form of cell therapy for graft protection in transplantation.