Regulatory T cells from allo- to xenotransplantation: Opportunities and challenges.

Regulatory T cells (Treg) are currently being evaluated in clinical allotransplantation for tolerance induction, with proven safety in humans with autoimmune diseases and graft-versus-host disease. A considerable amount of recent data suggests that additional factors may need to be validated, including the stability and commitment of newly discovered Treg subsets under inflammatory conditions, to further warrant safe and effective Treg-based therapeutic approaches. This review explores the opportunities and challenges of Treg-based cell therapy in xenotransplantation. The emerging new technologies for genetic modifications of the donor pig offer a major advantage for Treg therapy to improve xenograft protection. Particularly, the feasibility of (i) ex vivo expansion of donor (pig)-specific Treg for infusion, and (ii) development of Treg in situ for the life of the xenograft. Our understanding of the Treg biology and their role in xenograft protection, under the newly developed immunosuppressive protocols remains limited. The incidence of various Treg subpopulations in xenograft recipients and their suppressive efficacy across species barriers are largely unknown. Finally, deciphering the dynamics of Treg function, and their interaction with adaptive and innate immune cells are of critical importance to design safe, effective and clinically relevant Treg-based therapeutic approaches in xenotransplantation.