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Interleukin (IL)‐9‐producing CD4⁺ T cells are a novel subset of T helper (Th) cells that develops independently of the Th1, Th2, Th17 and regulatory T‐cell lineages. Similar to the murine model, transforming growth factor (TGF)‐β and IL‐4 directed human naive CD4⁺ T cells to produce IL‐9. Whereas IL‐4 suppressed TGF‐β‐induced Foxp3 expression, TGF‐β failed to inhibit IL‐4‐mediated upregulation of the Th2 transcription factor GATA‐3. Addition of IL‐1β, IL‐6, IL‐10, interferon (IFN)‐α, IFN‐β or IL‐21 to Th9‐polarizing conditions augmented Th9 differentiation, while the Th1‐associated cytokines IFN‐γ and IL‐27 partially suppressed IL‐9 production. Given that T cells are a primary source of IL‐21, IL‐21 expression was analyzed under Th9‐polarizing conditions in the context of inflammatory cytokines. Surprisingly, type I IFNs induced elevated levels of IL‐21, and blockade of IL‐21 abrogated their ability to …