Regulatory T Cells Suppress Development of Colitis, Blocking Differentiation of T-Helper 17 Into Alternative T-Helper 1 Cells

Background & AimsAlthough 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 (TR) cells in their development.MethodsWe performed adoptive transfer experiments to investigate the induction and suppression of colitis using naïve CD4+CD45RBhigh T cells and/or CD4+CD25+ TR cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/+ or Ly5.1/Ly5.2 congenic mice.ResultsWe observed 3 types of colitogenic CD4+ Th1 cells (interleukin [IL]-17A−interferon [IFN]-γ+): RORγt– classical Th1 cells that differentiated directly from naïve 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-17A–IFN-γ+) cells. In this pathway, CD4+CD25+ TR 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, TR 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.ConclusionsTh17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. TR cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.