Cheng Xiaodong, Zhao Zhao, Ventura Elvira, Gran Bruno, Shindler Kenneth S, Rostami Abdolmohamad
Department of Neurology, Jefferson Hospital for Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
J Neuroimmunol. 2007 Apr;185(1-2):75-86. doi: 10.1016/j.jneuroim.2007.01.012. Epub 2007 Feb 23.
Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is mediated by autoantigen-specific T-helper1 (Th1) cells. IL-12, an inducer of Th1 cell development, exerts immunomodulatory effects in EAE. Programmed death-1 (PD-1) and PD-1 ligand (PD-L), new members of the B7 superfamily of costimulatory molecules, play a critical role in regulating EAE. Whether the interaction of IL-12 and the PD-1/PD-L pathway regulates EAE is unclear. We have previously shown that IL-12 suppresses EAE induced by MOG35-55 in C57BL/6 mice, but not in IFN-gamma-deficient mice, suggesting that IFN-gamma is required for the inhibitory effects of IL-12 on EAE. In the current study, PD-L1 expression is up-regulated following IL-12 treatment in wild-type mice, but not in IFN-(-deficient EAE mice. Similarly, IL-12 induces IFN-gamma and PD-L1 expression in cultured MOG-specific T cells from wild-type mice but not from IFN-gamma-deficient mice. Furthermore, PD-L1 expression increased specifically in CD11b+ antigen presenting cells (APCs) after IL-12 administration. These data suggest that one mechanism of IL-12 suppression of EAE is mediated by PD-1/PD-L signaling downstream of IFN-gamma induction in CD11b+ APCs. The regulation of PD-1/PD-L1 may have potential therapeutic effects for EAE and MS.
实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症（MS）的一种动物模型，由自身抗原特异性辅助性T细胞1（Th1）介导。白细胞介素12（IL-12）是Th1细胞发育的诱导剂，在EAE中发挥免疫调节作用。程序性死亡1（PD-1）和PD-1配体（PD-L）是共刺激分子B7超家族的新成员，在调节EAE中起关键作用。IL-12与PD-1/PD-L途径的相互作用是否调节EAE尚不清楚。我们之前已经表明，IL-12可抑制C57BL/6小鼠中由MOG35-55诱导的EAE，但在干扰素-γ缺陷小鼠中则不能，这表明干扰素-γ是IL-12对EAE产生抑制作用所必需的。在当前研究中，野生型小鼠经IL-12处理后PD-L1表达上调，但在干扰素-γ缺陷的EAE小鼠中则不然。同样，IL-12可诱导野生型小鼠培养的MOG特异性T细胞中干扰素-γ和PD-L1表达，但不能诱导干扰素-γ缺陷小鼠的此类细胞表达。此外，给予IL-12后，PD-L1表达在CD11b+抗原呈递细胞（APC）中特异性增加。这些数据表明，IL-12抑制EAE的一种机制是由CD11b+ APC中干扰素-γ诱导下游的PD-1/PD-L信号介导的。PD-1/PD-L1的调节可能对EAE和MS具有潜在治疗作用。
