IκBζ regulates TH17 development by cooperating with ROR nuclear receptors
IκBζ regulates TH17 development by cooperating with ROR nuclear receptors
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DOI：
10.1038/nature08922
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发表时间：
2010-04-29
期刊：
影响因子：
64.8
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Okamoto, Kazuo;Iwai, Yoshiko;Takayanagi, Hiroshi
产生白细胞介素（IL）-17的辅助T（T（H）17）细胞是一种独特的T细胞亚群，其特征在于其在自身免疫性疾病中的病理作用（1-3）。IL-6和转化生长因子-β（TGF-β）诱导TH 17发育，其中孤儿核受体ROR γ t和ROR α具有不可或缺的作用（4-6）。然而，在不存在IL-6和TGF-β的情况下，ROR γ t或ROR α的异位表达仅导致适度的IL-17产生（5，7，8）。在这里，我们确定了一个核I κ B家族成员，I κ B zeta（由Nfkbiz基因编码），作为小鼠TH 17发育所需的转录因子。初始CD 4（+）T细胞中I κ B zeta的异位表达与ROR γ t或ROR α一起有效诱导T（H）17发育，即使在不存在IL-6和TGF-β的情况下。值得注意的是，Nfkbiz（-/-）小鼠在T（H）17发育方面存在缺陷，并且对实验性自身免疫性脑脊髓炎（EAE）具有抗性。I κ B zeta的T细胞内在功能通过转移Nfkbiz（-/-）CD 4（+）T细胞的Rag 2（-/-）小鼠对EAE的抗性清楚地证明。I κ B ζ与ROR γ t和RORa协同作用，通过直接结合IL 17 a基因的调控区来增强IL 17 a的表达。这项研究为T（H）17的转录机制提供了证据，并为针对自身免疫性疾病的新治疗策略提供了分子基础。
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.