Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases1,2,3. IL-6 and transforming growth factor-β (TGF-β) induce TH17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role4,5,6. However, in the absence of IL-6 and TGF-β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production5,7,8. Here we identify a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IκBζ in naive CD4+ T cells together with RORγt or RORα potently induces TH17 development, even in the absence of IL-6 and TGF-β. Notably, Nfkbiz-/- mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBζ 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, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying TH17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
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We are grateful to Y. Iwakura and T. Kitamura for providing Il17a-/- mice and retrovirus vectors, respectively. We also thank M. Shinohara, T. Negishi-Koga, M. Asagiri, T. Nakashima, N. Komatsu, M. Ohba, Y. Kunisawa, Y. Suzuki, S. Miyakoshi and T. Kunigami for discussion and assistance. This work was supported in part by Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid for Challenging Exploratory Research from JSPS, Grant-in-Aid for JSPS Fellows, Grants-in-Aid for GCOE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and ERATO, Takayanagi Osteonetwork Project from JST. It was also supported by grants from the Intramural Research Program of the NIEHS (Z01-ES-101586) (to A.M.J.), Takeda Life Science Foundation and Yokoyama Foundation for Clinical Pharmacology and the Ichiro Kanehara Foundation. Ka.O. is supported by JSPS Research Fellowships for Young Scientists.
This file contains Supplementary Figures 1-19 with legends, Supplementary Tables 1-2 and Supplementary References.
About this article
Nature Communications (2018)