While FOXP3+ regulatory T cell (Treg) dysfunction has been linked to human inflammatory bowel disease (IBD), molecular mechanisms for disease pathophysiology are unclear. The transcription factor FOXP3 via histone methyltransferase EZH2 suppresses inflammation in mice. Here, we tested the hypothesis that a physical FOXP3-EZH2 protein interaction is essential for gene co-repressive function critical for human Treg physiological functions.