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 gamma t (ROR gamma t) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of ROR gamma t(+) T cells express IL-17. We report here that ROR gamma t(+) T alpha beta cells include Foxp3(+) cells that coexist with IL-17-producing ROR gamma t(+) T alpha beta cells in all tissues examined. The Foxp3(+) ROR gamma t(+) T alpha beta express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3(+) to IL-17-producing ROR gamma t(+) T alpha beta 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 ROR gamma t(+) T cells express the gamma delta 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(+) ROR gamma t(+) T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in ROR gamma t(+) T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.