Conversion of Th17 into IL-17Aneg Regulatory T Cells: A Novel Mechanism in Prolonged Allograft Survival Promoted by Mesenchymal Stem Cell–Supported Minimized Immunosuppressive Therapy

The ultimate goal in transplantation medicine is the promotion of operational tolerance. Although Th cells of the Th17 type have been predominantly associated with rejection of allogeneic solid organ grafts, regulatory T (T(reg)) cells appear to foster operational tolerance. Induced T(reg) and Th17 cells have a higher lineage plasticity than has been recognized thus far. We found that when mesenchymal stem cells (MSCs) were used to induce long-term acceptance of allogeneic heart grafts in mice, the induction of T(reg) cells was preceded by development of a CD11b(hi)Gr1(int) myeloid-derived immunosuppressive cell-mediated Th17 response. Substantial suppression of Foxp3(+) T(reg) cell generation from retinoic acid receptor-related orphan receptor γ(-/-) T cells by MSCs revealed that retinoic acid receptor-related orphan receptor γ is a common factor in the differentiation of T(reg) and Th17 cells. Immunosuppressant mycophenolate mofetil treatment of enriched IL-17A(+) cells from MSC-primed allograft mouse recipients resulted in a reduction of IL-17A production and an increase in the Foxp3(+) T(reg) cell fraction. Furthermore, identification of IL-17A(+) Foxp3(+) double-positive and ex-IL-17-producing IL-17A(neg)Foxp3(+) T cells strongly argues for direct conversion of Th17 cells into T(reg) cells as the underlying mechanism of immune regulation in MSC-mediated allograft survival. The Th17 into T(reg) conversion identified in this study constitutes an important immunological mechanism by which MSC-induced myeloid-derived immunosuppressive cells mediate operational transplant tolerance. The possibility to create T(reg) cell-regulated operational tolerance in the absence of complete immune suppression provides strong clinical implications for cell therapy-assisted minimization protocols.