Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis

实验性自身免疫性脑脊髓炎 髓鞘少突胶质细胞糖蛋白 免疫学 自身免疫 脑脊髓炎 封锁 CD28 自身免疫性疾病 中心公差 周边公差 生物 T细胞 医学 免疫系统 抗体 多发性硬化 受体 内科学
作者
Alan D. Salama,Tanuja Chitnis,Jaime Imitola,Mohammed Javeed Ansari,Hisaya Akiba,Fumihiko Tushima,Miyuki Azuma,Hideo Yagita∥,Mohamed H. Sayegh,Samia J. Khoury
出处
期刊:Journal of Experimental Medicine [The Rockefeller University Press]
卷期号:198 (1): 71-78 被引量:486
标识
DOI:10.1084/jem.20022119
摘要

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

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