Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK
Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK
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DOI：
10.1182/blood-2008-12-192914
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发表时间：
2009-06-25
期刊：
影响因子：
20.3
通讯作者：
Sun, Shao-Cong
中科院分区：
文献类型：
--
作者：
Jin, Wei;Zhou, Xiao-Fei;Sun, Shao-Cong
Th 17细胞在介导自身免疫性疾病中发挥重要作用，但其分化的分子机制尚不完全清楚。我们在这里表明，NF-κ B诱导激酶（NIK），这是已知的调节B细胞成熟和淋巴器官，是重要的诱导Th 17细胞。NIK缺陷型初始CD 4 T细胞在向Th 17细胞的分化中减弱，尽管它们能够定向于其他效应谱系。因此，NIK基因敲除小鼠对实验性自身免疫性脑脊髓炎具有抗性，这是一种涉及Th 17细胞功能的疾病模型。在用NIK缺陷型T细胞重建的Rag 2敲除小鼠中也检测到这种表型，证实了T细胞内在缺陷。我们进一步表明，NIK介导的协同激活STAT 3的T细胞受体和IL-6受体信号。NIK缺陷减弱了参与Th 17定型程序的STAT 3的激活和STAT 3靶基因的诱导。这些发现确立了NIK作为调节Th 17分化和实验性自身免疫性脑炎诱导的重要信号传导因子。（血。2009; 113：6603-6610）
Th17 cells play an important role in mediating autoimmune diseases, but the molecular mechanism underlying Th17 differentiation is incompletely understood. We show here that NF-kappa B-inducing kinase (NIK), which is known to regulate B-cell maturation and lymphoid organogenesis, is important for the induction of Th17 cells. NIK-deficient naive CD4 T cells are attenuated in the differentiation to Th17 cells, although they are competent in committing to the other effector lineages. Consistently, NIK knockout mice are resistant to experimental autoimmune encephalomyelitis, a disease model that involves the function of Th17 cells. This phenotype was also detected in Rag2 knockout mice reconstituted with NIK-deficient T cells, confirming a T-cell intrinsic defect. We further show that NIK mediates synergistic activation of STAT3 by T-cell receptor and IL-6 receptor signals. NIK deficiency attenuates activation of STAT3 and induction of STAT3 target genes involved in Th17-commitment program. These findings establish NIK as an important signaling factor that regulates Th17 differentiation and experimental autoimmune encephalitis induction. (Blood. 2009; 113: 6603-6610)