The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells

The molecular mechanisms by which TGF-β and interleukin 4 (IL-4) signaling control the differentiation of IL-9-producing CD4(+) T (T(H)9) cells remain incompletely understood. We show here that the DNA-binding inhibitor Id3 regulated Th9 cell differentiation, as deletion of Id3 increased IL-9 production from CD4(+) T cells. Mechanistically, TGF-β1 and IL-4 down-regulated Id3 expression and this process required the kinase TAK1. Reduction of Id3 expression enhanced the binding of the transcription factors E2A and GATA-3 in the Il9 promoter region, which promoted Il9 gene transcription. Importantly, Id3 control of T(H)9 cells differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo, and also in human CD4(+) T cells in vitro. Thus, this study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates T(H)9 cell differentiation.