T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity
T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity
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DOI：
10.4049/jimmunol.178.3.1341
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Lovett-Racke, Amy E.
中科院分区：
文献类型：
--
作者：
Gocke, Anne R.;Cravens, Petra D.;Lovett-Racke, Amy E.
产生IL-17的T细胞（Th 17）最近被认为与实验性自身免疫性脑脊髓炎（EAE）的发病机制有关，EAE是人类多发性硬化症的动物模型。然而，对调控这些细胞的转录因子知之甚少。尽管转录因子T-bet在产生IFN-γ的CD 4（+）Th 1淋巴细胞的分化中起着重要作用，但T-bet在Th 17细胞分化中的潜在作用还不完全清楚。在这项研究中，治疗性给予T-bet特异性小干扰RNA显著改善了已建立的EAE的临床病程。改善的临床过程与CNS中表达IL-17的新分化T细胞的抑制以及髓鞘碱性蛋白特异性Th 1自身反应性T细胞的抑制有关。此外，发现T-bet直接调节IL-23 R的转录，并且在这样做时，影响Th 17细胞的命运，Th 17细胞的生存依赖于最佳IL-23产生。我们现在首次表明，抑制T-bet可以通过限制自身反应性Th 1细胞的分化以及通过调节IL-23 R抑制致病性Th 17细胞来改善EAE。
IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalorayelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-gamma-producing CD4(+) Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.