T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ
T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ
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DOI：
10.1016/j.immuni.2007.11.016
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发表时间：
2008-01-01
期刊：
影响因子：
32.4
通讯作者：
Dong, Chen
中科院分区：
文献类型：
--
作者：
Yang, Xuexian O.;Pappu, Bhanu P.;Dong, Chen
T细胞功能分化是由谱系特异性转录因子介导的。辅助性T细胞17(Th17)最近被确定为一种独特的Th细胞系，介导组织炎症。视黄酸受体相关孤儿受体γ(ROR-γ)可调节Th17细胞分化；然而，ROR-γ缺乏并不能完全消除Th17细胞因子的表达。在此，我们报道了Th17细胞在转化生长因子-β和白介素6(IL-6)诱导下高表达另一种相关的核受体--ROR-α，该受体依赖于信号转导和转录激活因子3。过表达的ROR-α促进了Th17的分化，可能是通过II17-II17f基因座保守的非编码序列2。RORα缺乏导致体内和体外IL-17表达降低。此外，RORα和RORγ的共同表达协同导致Th17细胞分化更大。RORα和ROR伽马的双重缺陷在全球范围内损害了Th17代，并完全保护小鼠免受实验性自身免疫性脑脊髓炎的影响。因此，Th17的分化是由两个谱系特异性的核受体--RORα和ROR Gamma引导的。
T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in II17-II17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.