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On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions 1. Recently a subset of T cells, distinct from T helper (TH)1 and TH2 cells, producing interleukin (IL)-17 (TH17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation 2-5. We and others have shown that transforming growth factor (TGF)-[beta] and IL-6 together induce the differentiation of TH17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3 regulatory T cells (Treg cells) or TH17 cells 6-9. Whereas TGF-[beta] induces Foxp3 and generates Treg cells, IL-6 inhibits the generation of Treg cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for TH17 and Treg cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a TH17 response and their peripheral repertoire is dominated by Foxp3 Treg cells. However, deletion of Treg cells leads to the reappearance of TH17 cells in Il6-/- mice, suggesting an additional pathway by which TH17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-[beta] to induce TH17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a TH17 response.

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