The molecular mechanisms by which signaling via transforming growth factor-β (TGF-β) and interleukin 4 (IL-4) control the differentiation of CD4 + IL-9-producing helper T cells (T H 9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated T H9 differentiation, as deletion of Id3 increased IL-9 production from CD4+ T cells. Mechanistically, TGF-β1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the transcription factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3-mediated control of T H9 differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo and also in human CD4+ T cells in vitro. Thus, our study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates T H 9 differentiation.
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