IL-21 initiates an alternative pathway to induce proinflammatory T(H17) cells. This study shows that IL-21, a member of the IL-2 cytokine family, can substitute for IL-6 in the differentiation of T(H17) cells in the absence of IL-6. IL-6 and IL-21 both cooperate with TGF-β to induce T(H17) cells, suggesting that T(H17) cells can be generated through multiple pathways. In IL-6-deficient mice, T(H17) cells are not typically generated, but their presence can be restored by depleting regulatory T cells (T(reg)). The study also demonstrates that IL-21 is essential for the differentiation of T(H17) cells in the absence of IL-6, as IL-21 receptor-deficient mice show reduced T(H17) cell differentiation. IL-21 promotes the production of IL-17 and the transcription factor ROR-γt, which are critical for T(H17) cell differentiation. Additionally, IL-21 can amplify T(H17) differentiation through a feedback loop, where T(H17) cells produce more IL-21, further enhancing their differentiation. The study also highlights the role of IL-21 in autoimmune diseases, suggesting that targeting IL-21 could help balance the immune response between pathogenic T(H17) cells and regulatory T cells. The findings indicate that IL-21 and IL-6 both play crucial roles in the development of T(H17) cells, with IL-21 providing an alternative pathway when IL-6 is absent.IL-21 initiates an alternative pathway to induce proinflammatory T(H17) cells. This study shows that IL-21, a member of the IL-2 cytokine family, can substitute for IL-6 in the differentiation of T(H17) cells in the absence of IL-6. IL-6 and IL-21 both cooperate with TGF-β to induce T(H17) cells, suggesting that T(H17) cells can be generated through multiple pathways. In IL-6-deficient mice, T(H17) cells are not typically generated, but their presence can be restored by depleting regulatory T cells (T(reg)). The study also demonstrates that IL-21 is essential for the differentiation of T(H17) cells in the absence of IL-6, as IL-21 receptor-deficient mice show reduced T(H17) cell differentiation. IL-21 promotes the production of IL-17 and the transcription factor ROR-γt, which are critical for T(H17) cell differentiation. Additionally, IL-21 can amplify T(H17) differentiation through a feedback loop, where T(H17) cells produce more IL-21, further enhancing their differentiation. The study also highlights the role of IL-21 in autoimmune diseases, suggesting that targeting IL-21 could help balance the immune response between pathogenic T(H17) cells and regulatory T cells. The findings indicate that IL-21 and IL-6 both play crucial roles in the development of T(H17) cells, with IL-21 providing an alternative pathway when IL-6 is absent.