The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma
The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma
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DOI：
10.1016/j.jneuroim.2007.01.012
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发表时间：
2007-04-01
影响因子：
3.3
通讯作者：
Rostami, Abdolmohamad
中科院分区：
文献类型：
--
作者：
Cheng, Xiaodong;Zhao, Zhao;Rostami, Abdolmohamad
实验性自身免疫性脑脊髓炎（EAE）是一种多发性硬化（MS）的动物模型，由自身抗原特异性辅助性T细胞1（Th 1）介导。IL-12是Th 1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中起着关键作用。IL-12和PD-1/PD-L通路的相互作用是否调节EAE尚不清楚。我们先前已经表明IL-12抑制C57 BL/6小鼠中由MOG 35 -55诱导的EAE，但在IFN-γ缺陷小鼠中不抑制，这表明IFN-γ是IL-12对EAE的抑制作用所必需的。在本研究中，野生型小鼠经IL-12治疗后PD-L1表达上调，但IFN-β缺陷型EAE小鼠中未上调。类似地，IL-12诱导来自野生型小鼠但不来自IFN-γ缺陷型小鼠的培养的MOG特异性T细胞中的IFN-γ和PD-L1表达。此外，IL-12给药后，CD 11b+抗原呈递细胞（APC）中的PD-L1表达特异性增加。这些数据表明，IL-12抑制EAE的一种机制是由CD 11b + APC中IFN-γ诱导下游的PD-1/PD-L信号传导介导的。PD-1/PD-L1的调节可能对EAE和MS具有潜在的治疗作用。（c）2007 Elsevier B. V.保留所有权利。
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. (c) 2007 Elsevier B.V. All rights reserved.