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

Th17 and regulatory T (T_reg) cells are integral in maintaining immune homeostasis and Th17-T_reg misbalance associates with inflammation.

We demonstrate that in addition to natural (n)T_reg and induced (i)T_reg 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-17A⁺Foxp3⁺ double-positive and ex-IL-17-producing IL-17A^-Foxp3⁺ T cells to be the underlying mechanism of immune regulation in mesenchymal stem cell-mediated prolonged allograft survival. Further, we identified accumulation of IL17A⁺Foxp3⁺ and ex-Th17 Foxp3⁺ cells in tumor bearing mice, indicating progressive direct Th17-into-T_reg 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 T_reg cell induction. TGF-b₁ induced Foxp3 expression was reduced in ROR-g ^-/- cells. Further, tumor bearing ROR-g^-/- mice showed significantly less Foxp3⁺ T_reg 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 IL17⁺FoxP3⁺ subset, and a significant correlation between tumor-associated Th17 and T_reg 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.