Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells

Background & Aims: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4 ⁺CD25⁺ regulatory T (T_R) cells in their development. Methods: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using nave CD4⁺CD45RB ^high T cells and/or CD4⁺CD25⁺ T_R cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/⁺ or Ly5.1/Ly5.2 congenic mice. Results: We observed 3 types of colitogenic CD4⁺ Th1 cells (interleukin [IL]-17A^-interferon [IFN]-γ⁺): RORγt classical Th1 cells that differentiated directly from nave T cells; RORγt ⁺ Th1-like cells; and RORγt alternative Th1 cells that were terminally differentiated from RORγt⁺ cells via Th17 (IL-17A⁺IFN-γ), Th17/Th1 (IL-17A⁺IFN- γ⁺), or Th1-like (IL-17AIFN-γ⁺) cells. In this pathway, CD4⁺CD25⁺ T_R cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T_R cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. Conclusions: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T_R cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.