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Nature. 2007 Jul 26;448(7152):484-487. doi: 10.1038/nature05970. Epub 2007 Jun 20.

IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.

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Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Contributed equally


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(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. 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. 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.

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