IκBζ and ROR nuclear receptors synergistically promote Th17 development. Interleukin (IL)-6 and transforming growth factor-β (TGF-β) induce Th17 cell differentiation, in which the ROR nuclear receptors, RORγt and RORα, have an indispensable role. The expression of IκBζ is induced by the combination of IL-6 and TGF-β. IκBζ induction is mediated by signal transducer and activator of transcription 3 (Stat3), but not RORγt. IκBζ and ROR nuclear receptor bind directly to the CNS2 region of the Il17 promoter and cooperatively activate the Il17 promoter. Notably, recruitment of IκBζ to the CNS2 region was dependent on RORγt, suggesting that the binding of both IκBζ and ROR nuclear receptors to the Il17 promoter leads to an efficient recruitment of transcriptional coactivators having histone acetylase activity. CNS2, conserved noncoding sequence 2; MHC II, major histocompatibility complex class II; ROR, retinoid-related orphan receptor; TCR, T-cell receptor; Th, helper T.