On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T_H)1 and T_H2 cells, producing interleukin (IL)-17 (T_H17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation^,,,. We and others have shown that transforming growth factor (TGF)-β and IL-6 together induce the differentiation of T_H17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3⁺ regulatory T cells (T_reg cells) or T_H17 cells^,,,. Whereas TGF-β induces Foxp3 and generates T_reg cells, IL-6 inhibits the generation of T_reg cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T_H17 and T_reg cells. Here we show that IL-6-deficient (Il6^-/-) mice do not develop a T_H17 response and their peripheral repertoire is dominated by Foxp3⁺ T_reg cells. However, deletion of T_reg cells leads to the reappearance of T_H17 cells in Il6^-/- mice, suggesting an additional pathway by which T_H17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-β to induce T_H17 cells in naive Il6^-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T_H17 response.