Ex-Th17 Foxp3+ T cells - a novel subset of Foxp3+ T cells induced in cancer

Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg misbalance associates with inflammation. We demonstrate that in addition to natural (n)Treg and induced (i)Treg cells developed from naïve precursors, Th17 cells are a novel source of Foxp3 cells by converting into ex-Th17 Foxp3 cells, and this helps to reconcile the contradictory information about the relevance in particularly of Th17 subset in immune surveillance. We identified IL-17AFoxp3 double-positive and ex-IL17-producing IL-17AFoxp3 T cells to be the underlying mechanism of immune regulation in mesenchymal stem cell-mediated prolonged allograft survival. Further, we identified accumulation of IL17AFoxp3 and ex-Th17 Foxp3 cells in tumor bearing mice, indicating progressive direct Th17-into-Treg cell conversion as a novel phenomenon in cancer. Moreover, we determined the importance of the Th17 cell plasticity for tumor induction and/or progression in ROR-g mice. Our data indicate that RORgt is required not only for Th17 development, but also for effective Treg cell induction. TGF-b1 induced Foxp3 expression was reduced in ROR-g -/cells. Further, tumor bearing RORg mice showed significantly less Foxp3 Treg cells, but higher IFNg Tcells compared to wild type animals. Increased infiltration of IL17 and FoxP3 CD4 T cells in the human ovarian cancer ascites, with the presence of a distinct IL17FoxP3 subset, and a significant correlation between tumor-associated Th17 and Treg cells demonstrates the existence of Th17-Foxp3 + T cell inter-relationship in cancer patients. Yin-yang of IL17 and Foxp3 is important principle for improved clinical approaches targeting responses against self, allo and/or neo-self.