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.