YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity

Regulatory T (T-reg) cells are essential for maintenance of immune homeostasis. Foxp3 is the key transcription factor for T-reg-cell differentiation and function; however, molecular mechanisms for its negative regulation are poorly understood. Here we show that YY1 expression is lower in T-reg cells than T-conv cells, and its overexpression causes a marked reduction of Foxp3 expression and abrogation of suppressive function of T-reg cells. YY1 is increased in T-reg cells under inflammatory conditions with concomitant decrease of suppressor activity in dextran sulfate-induced colitis model. YY1 inhibits Smad3/4 binding to and chromatin remodelling of the Foxp3 locus. In addition, YY1 interrupts Foxp3-dependent target gene expression by physically interacting with Foxp3 and by directly binding to the Foxp3 target genes. Thus, YY1 inhibits differentiation and function of T-reg cells by blocking Foxp3.