期刊
NATURE
卷 464, 期 7293, 页码 1381-U13出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08922
关键词
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资金
- Japan Society for the Promotion of Science (JSPS)
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- ERATO
- JST
- NIEHS [Z01-ES-101586]
- Takeda Life Science Foundation
- Yokoyama Foundation
- Ichiro Kanehara
- Grants-in-Aid for Scientific Research [21390088] Funding Source: KAKEN
Interleukin (IL)-17-producing helper T (T(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-beta (TGF-beta) induce TH17 development, in which the orphan nuclear receptors, ROR gamma t and ROR alpha, have an indispensable role(4-6). However, in the absence of IL-6 and TGF-beta, the ectopic expression of ROR gamma t or ROR alpha leads to only a modest IL-17 production(5,7,8). Here we identify a nuclear I kappa B family member, I kappa B zeta (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of I kappa B zeta in naive CD4(+) T cells together with ROR gamma t or ROR alpha potently induces T(H)17 development, even in the absence of IL-6 and TGF-beta. Notably, Nfkbiz(-/-) mice have a defect in T(H)17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of I kappa B zeta was clearly demonstrated by the resistance to EAE of the Rag2(-/-) mice into which Nfkbiz(-/-) CD4(+) T cells were transferred. In cooperation with ROR gamma t and RORa, I kappa B zeta enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T(H)17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
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