IκBθ regulates [T.sub.H]17 development by cooperating with ROR nuclear receptors

Interleukin (IL)-17-producing helper T ([T.sub.H]17) 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.sub.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 IκB family member, IκBθ (encoded by the Nfkbiz gene), as a transcription factor required for [T.sub.H]17 development in mice. The ectopic expression of IκBθ in naive [CD4.sup.+] T cells together with RORγt or RORα potently induces [T.sub.H]17 development, even in the absence of IL-6 and TGF-β. Notably, [Nfkbiz.sup.-/-] mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBθ was clearly demonstrated by the resistance to EAE of the [Rag2.sup.-/-] mice into which [Nfkbiz.sup.-/-] [CD4.sup.+] T cells were transferred. In cooperation with RORγt and RORα, IκBθ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying [T.sub.H]17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
IκBθ is a nuclear protein homologous to Bcl3, which interacts with the NF-κB subunit via the ankyrin repeat domain (ARD) (9,10). In macrophages, IκBθ induced by Toll-like receptor (TLR) stimulation [...]