The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses TH2 differentiation

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Abstract
The mechanisms of TGF-β-mediated inhibition of TH2 differentiation remain unclear. Nakayama and colleagues show that TGF-β induces the transcription factor Sox4, which negatively regulates the transcription factor GATA-3 by two independent mechanisms. Sox4 is a transcription factor that regulates various developmental processes. Here we show that Sox4 was induced by TGF-β and negatively regulated the transcription factor GATA-3, the master regulator of function of T helper type 2 (TH2) cells, by two distinct mechanisms. First, Sox4 bound directly to GATA-3, preventing its binding to GATA-3 consensus DNA sequences. Second, Sox4 bound to the promoter region of the gene encoding interleukin 5 (IL-5), a TH2 cytokine, and prevented binding of GATA-3 to this promoter. TH2 cell–driven airway inflammation was modulated by alterations in Sox4 expression. Thus, Sox4 acted as a downstream target of TGF-β to inhibit GATA-3 function, TH2 differentiation and TH2 cell–mediated inflammation.