Inhibitor of kappa B (I kappa B)-zeta, a member of the nuclear I kappa B family of proteins, is induced by the transforming growth factor (TGF)-beta signaling pathway and plays a pivotal role in maintaining the balance of T helper (Th) cell subsets. I kappa B-zeta deficiency results in reduced percentages of Th17 cells and increased percentages of Th1 cells. In this study, the effects of I kappa B-zeta deficiency on T-cell subsets were examined further. The data showed that I kappa B-zeta-deficient T cells had a high capacity for generation of regulatory T cells (Tregs) when T cells were cultured under TGF-beta stimulation in the presence of cytokine-neutralizing antibodies. Mechanistically, I kappa B-zeta itself negatively regulated activation of the Foxp3 promoter in a nuclear factor of kappaB-dependent manner. Thus, this study showed that I kappa B-zeta controlled Treg differentiation. (C) 2015 The Author. Published by Elsevier Inc.