The study investigates the role of IL-21 in the differentiation of proinflammatory T helper (TH)17 cells. IL-6 and TGF-β are known to induce TH17 cells, with IL-6 inhibiting the generation of regulatory T (Treg) cells and promoting TH17 cell differentiation. In IL-6-deficient (Il6−/−) mice, Treg cells dominate the peripheral repertoire, but depletion of Treg cells in these mice leads to the re-emergence of TH17 cells, suggesting an alternative pathway for TH17 cell generation. The researchers found that IL-21, a member of the IL-2 cytokine family, works in concert with TGF-β to induce TH17 cells in naive Il6−/− T cells. IL-21 receptor-deficient T cells are defective in generating a TH17 response. The study also shows that IL-21 can substitute for IL-6 in inducing ROR-γt expression and IL-17 production, indicating its role in the differentiation of TH17 cells. In vivo, TGF-β plus IL-21 can drive TH17 cell differentiation independently of IL-6, and neutralizing IL-21 in Treg-depleted Il6−/− mice abrogates TH17 cell generation. The findings suggest that IL-21 and TGF-β form an additional pathway for TH17 cell generation, and targeting IL-21 may help balance TH17 and Treg cells in autoimmune diseases.The study investigates the role of IL-21 in the differentiation of proinflammatory T helper (TH)17 cells. IL-6 and TGF-β are known to induce TH17 cells, with IL-6 inhibiting the generation of regulatory T (Treg) cells and promoting TH17 cell differentiation. In IL-6-deficient (Il6−/−) mice, Treg cells dominate the peripheral repertoire, but depletion of Treg cells in these mice leads to the re-emergence of TH17 cells, suggesting an alternative pathway for TH17 cell generation. The researchers found that IL-21, a member of the IL-2 cytokine family, works in concert with TGF-β to induce TH17 cells in naive Il6−/− T cells. IL-21 receptor-deficient T cells are defective in generating a TH17 response. The study also shows that IL-21 can substitute for IL-6 in inducing ROR-γt expression and IL-17 production, indicating its role in the differentiation of TH17 cells. In vivo, TGF-β plus IL-21 can drive TH17 cell differentiation independently of IL-6, and neutralizing IL-21 in Treg-depleted Il6−/− mice abrogates TH17 cell generation. The findings suggest that IL-21 and TGF-β form an additional pathway for TH17 cell generation, and targeting IL-21 may help balance TH17 and Treg cells in autoimmune diseases.