IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells

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 (T-H) 1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) 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 T(H)17 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(H)17 cells(6-9). Whereas TGF-beta 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(H)17 and T-reg cells. Here we show that IL-6-deficient (Il6(-/-)) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3(+) T-reg cells. However, deletion of T-reg cells leads to the reappearance of T(H)17 cells in Il6(-/-) mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6(-/-) T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.