In vivo equilibrium of proinflammatory IL-17(+) and regulatory IL-10(+) Foxp3(+) RORγt(+) T cells

The nuclear hormone receptor retinoic acid receptor–related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt(+) T cells express IL-17. We report here that RORγt(+) Tαβ cells include Foxp3(+) cells that coexist with IL-17–producing RORγt(+) Tαβ cells in all tissues examined. The Foxp3(+) RORγt(+) Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3(+) to IL-17–producing RORγt(+) Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt(+) T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17–producing and regulatory Foxp3(+) RORγt(+) T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt(+) T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.