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

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 (Treg) cells appear to foster operational tolerance. Induced Treg 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 Treg cells was preceded by development of a CD11bhiGr1int myeloid–derived immunosuppressive cell–mediated Th17 response. Substantial suppression of Foxp3+ Treg 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 Treg 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+ Treg cell fraction. Furthermore, identification of IL-17A+ Foxp3+ double-positive and ex–IL-17–producing IL-17AnegFoxp3+ T cells strongly argues for direct conversion of Th17 cells into Treg cells as the underlying mechanism of immune regulation in MSC-mediated allograft survival. The Th17 into Treg 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 Treg cell–regulated operational tolerance in the absence of complete immune suppression provides strong clinical implications for cell therapy–assisted minimization protocols.

Therapeutic effects of Wharton jelly‐derived mesenchymal stem cells on rat abortion models

“…In vitro studies have shown that MSC can induce Tregs of the peripheral lymphoid system expansion and differentiation, which inhibits Th17 cell differentiation and functions. 31 It has been shown that intravenous infusion of MSC could change the Th1/Th2 balance, thus contributing to prolonged cardiac allograft survival time. MSC can inhibit Th17 cell activity, thus reducing IL-17 expression and inflammatory cell infiltration in the central nervous system.…”

(Compl)Ex-Th17–Tregcell inter-relationship

“…3,4 Most importantly, MDSCs promote IL17 C FoxP3 C CD4 C Th cell induction and can skew IL17 C FoxP3 ¡ CD4 C cells toward IL17 ¡ FoxP3 C CD4 C cells. 45 When immune homeostasis is disturbed in tissue malfunction, inflammation occurs through activating tissue-resident macrophages and/or recruiting additional myeloid cells.…”

“…PGE 2 has emerged as one key molecule in MDSC biology and appears to be the common denominator of diverse settings in the induction of MDSCs. 4,46 The most prominent cell type to induce MDSCs are cancerous cells. Additionally, bone marrow derived stromal cells, mesenchymal stem cells 4 or adipose cells 47 can also reprogram myeloid cells upon perturbed homeostasis (see Fig.…”

“…4,46 The most prominent cell type to induce MDSCs are cancerous cells. Additionally, bone marrow derived stromal cells, mesenchymal stem cells 4 or adipose cells 47 can also reprogram myeloid cells upon perturbed homeostasis (see Fig. 1 47 MDSCs inherently express factors and cytokines that instruct the development and plasticity of Th17 or T reg cells.…”

Microbiota activated CD103 DCS stemming from oral microbiota adaptation specifically drive T17 proliferation and activation.

“…This is understandable because it's already been shown in arthritis, transplantation and gut disease models that Th17 cells can convert to Tregs and visa-versa (Komatsu et al, 2014;Obermajer et al, 2014;Omenetti and Pizarro, 2015). The gut is such a dynamic, ever-changing environment that plasticity in the effector immune population is essential.…”