BACKGROUND Many lines of evidence suggest that accumulation of aggregated alpha-synuclein (αSYN) in the Parkinson's disease (PD) brain causes infiltration of T cells. However, in which ways the stationary brain cells interact with the T cells remain elusive. Here, we identify astrocytes as potential antigen-presenting cells capable of activating T cells in the PD brain. Astrocytes are a major component of the nervous system, and accumulating data indicate that astrocytes can play a central role during PD progression. METHODS To investigate the role of astrocytes in antigen presentation and T-cell activation in the PD brain, we analyzed post mortem brain tissue from PD patients and controls. Moreover, we studied the capacity of cultured human astrocytes and adult human microglia to act as professional antigen-presenting cells following exposure to preformed αSYN fibrils. RESULTS Our analysis of post mortem brain tissue demonstrated that PD patients express high levels of MHC-II, which correlated with the load of pathological, phosphorylated αSYN. Interestingly, a very high proportion of the MHC-II co-localized with astrocytic markers. Importantly, we found both perivascular and infiltrated CD4+ T cells to be surrounded by MHC-II expressing astrocytes, confirming an astrocyte T cell cross-talk in the PD brain. Moreover, we showed that αSYN accumulation in cultured human astrocytes triggered surface expression of co-stimulatory molecules critical for T-cell activation, while cultured human microglia displayed very poor antigen presentation capacity. Notably, intercellular transfer of αSYN/MHC-II deposits occurred between astrocytes via tunneling nanotubes, indicating spreading of inflammation in addition to toxic protein aggregates. CONCLUSIONS In conclusion, our data from histology and cell culture studies suggest an important role for astrocytes in antigen presentation and T-cell activation in the PD brain, highlighting astrocytes as a promising therapeutic target in the context of chronic inflammation.

中文翻译：

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星形胶质细胞具有在帕金森氏病脑中充当抗原呈递细胞的能力。

背景技术许多证据表明聚集的α-突触核蛋白（αSYN）在帕金森氏病（PD）脑中的积累引起T细胞的浸润。但是，静止的脑细胞与T细胞相互作用的方式仍然难以捉摸。在这里，我们将星形胶质细胞鉴定为能够激活PD脑中T细胞的潜在抗原呈递细胞。星形胶质细胞是神经系统的主要组成部分，越来越多的数据表明，星形胶质细胞可以在PD进程中发挥重要作用。方法为了研究星形胶质细胞在PD脑中抗原呈递和T细胞活化中的作用，我们分析了PD患者和对照的死后脑组织。此外，我们研究了培养的人类星形胶质细胞和成年人类小胶质细胞暴露于预先形成的αSYN原纤维后充当专业抗原呈递细胞的能力。结果我们对尸体脑组织的分析表明，PD患者表达高水平的MHC-II，这与病理性磷酸化αSYN的负荷有关。有趣的是，很高比例的MHC-II与星形细胞标记共定位。重要的是，我们发现血管周围和浸润的CD4 + T细胞都被表达MHC-II的星形胶质细胞包围，这证实了PD脑中星形胶质细胞T细胞的串扰。此外，我们发现培养的人类星形胶质细胞中的αSYN积累触发了对T细胞活化至关重要的共刺激分子的表面表达，而培养的人小胶质细胞显示出非常差的抗原呈递能力。值得注意的是，αSYN/ MHC-II沉积物的细胞间转移是通过穿隧纳米管在星形胶质细胞之间发生的，这表明除了有毒蛋白质聚集体之外，炎症还在蔓延。结论总之，我们从组织学和细胞培养研究获得的数据表明，星形胶质细胞在PD脑中的抗原呈递和T细胞活化中起着重要作用，突出了星形胶质细胞在慢性炎症中作为有希望的治疗靶标的作用。