Gocke Anne R, Cravens Petra D, Ben Li-Hong, Hussain Rehana Z, Northrop Sara C, Racke Michael K, Lovett-Racke Amy E
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
J Immunol. 2007 Feb 1;178(3):1341-8. doi: 10.4049/jimmunol.178.3.1341.
IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (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.
产生白细胞介素-17的T细胞（Th17细胞）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是人类疾病多发性硬化症的一种动物模型。然而，对于调节这些细胞的转录因子却知之甚少。虽然转录因子T-bet在产生干扰素-γ的CD4(+) Th1淋巴细胞分化中起着至关重要的作用这一点很明确，但T-bet在Th17细胞分化中的潜在作用尚未完全了解。在本研究中，给予针对T-bet的小干扰RNA进行治疗性给药显著改善了已建立的EAE的临床病程。临床病程的改善与中枢神经系统中表达白细胞介素-17的新分化T细胞的抑制以及髓鞘碱性蛋白特异性Th1自身反应性T细胞的抑制有关。此外，发现T-bet直接调节白细胞介素-23受体的转录，并由此影响Th17细胞的命运，Th17细胞的存活依赖于最佳的白细胞介素-23产生。我们现在首次表明，抑制T-bet通过限制自身反应性Th1细胞的分化以及通过调节白细胞介素-23受体抑制致病性Th17细胞来改善EAE。
