title: Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy.
abstract: 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.
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany obermajern2@upmc.edu marc.dahlke@ukr.de.
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Popp
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Yorick
authors.initials: Y
authors.lastname: Soeder
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Haarer
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Dahlke
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D009173:Mycophenolic Acid