Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
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DOI：
10.1172/jci36470
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发表时间：
2009-01-01
影响因子：
15.9
通讯作者：
Hunot, Stephane
中科院分区：
文献类型：
--
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
帕金森病（Parkinson disease，PD）是一种以多巴胺神经元缺失为特征的神经退行性疾病。越来越多的证据表明，多巴胺能细胞死亡是由先天免疫系统的影响。然而，适应性免疫系统在PD中的致病作用仍然是个谜。我们发现，在死后的人类PD标本和1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）小鼠PD模型中，在神经元变性过程中，CD 8（+）和CD 4（+）T细胞而不是B细胞侵入了脑。我们进一步证明，MPTP诱导的多巴胺能细胞死亡显着减弱的成熟T淋巴细胞在2个不同的免疫缺陷小鼠品系（Rag 1（-/-）和Tcrb（-/-）小鼠）的情况下。重要的是，在缺乏CD 4的小鼠以及用FasL缺陷的脾细胞重建的Rag 1（-/-）小鼠中观察到MPTP诱导的多巴胺能细胞死亡的类似衰减。然而，缺乏CD 8的小鼠和用IFN-γ缺陷的脾细胞重建的Rag 1（-/-）小鼠没有受到保护。这些数据表明，T细胞介导的多巴胺能毒性几乎完全由CD 4（+）T细胞仲裁，并且需要FasL而不是IFN γ的表达。此外，我们的数据可能为靶向免疫系统的适应性臂作为PD的治疗策略提供了理论基础。
Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8(+) and CD4(+) T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1(-/-) and Tcrb(-/-) mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1(-/-) mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1(-/-) mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4(+) T cells and requires the expression of FasL but not IFN gamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.