IκBη regulates T_H 17 development by cooperating with ROR nuclear receptors

Interleukin (IL)-17-producing helper T (T_H17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases^1-3. IL-6 and transforming growth factor-Β (TGF-Β) induce T H 17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role^4-6. However, in the absence of IL-6 and TGF-Β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production^5,7,8. Here we identify a nuclear IB family member, IB (encoded by the Nfkbiz gene), as a transcription factor required for T_H17 development in mice. The ectopic expression of IB in naive CD⁴⁺ T cells together with RORγt or RORα potently induces T H 17 development, even in the absence of IL-6 and TGF-Β. Notably, Nfkbiz^-/- mice have a defect in T_H17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IB was clearly demonstrated by the resistance to EAE of the Rag2^-/- mice into which Nfkbiz^-/- CD⁴⁺T cells were transferred. In cooperation with RORγt and RORα, IB enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T_H17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.