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IL-9 is a proallergic cytokine produced by a newly proposed Th cell subset, Th9. Th9 cells can be generated by treatment of naive T cells with TGF-β and IL-4 in vitro. However, it is still not clear how TGF-β signaling regulates Th9 differentiation. In this study, we demonstrate that Smad2 and Smad4, two transcriptional factors activated by TGF-β signaling, are required for Th9 differentiation in vitro. Deficiency of Smad2 or Smad4 in T cells resulted in impaired IL-9 expression, which was coincident with enrichment of repressive chromatin modification histone H3 K27 trimethylation and enhanced EZH2 binding to the Il9 locus. Pharmacologic inhibition of EZH2 partially rescued IL-9 production in Smad-deficient Th9 cells. Smad proteins may displace EZH2 directly from the Il9 locus, because Smad2 and Smad4 can bind EZH2. Our data shed light on the molecular mechanisms underlying Th9 cell differentiation, revealing that the TGF-β-Smad2/4-signaling pathway regulates IL-9 production through an epigenetic mechanism.

Cutting Edge: Smad2 and Smad4 Regulate TGF-β–Mediated Il9 Gene Expression via EZH2 Displacement