Neuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Biocentre, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
Institute for Neuropathology and Centre for Biological Signaling Studies, University of Freiburg, 79106 Freiburg, Germany.
Nat Commun. 2017 Apr 24;8:14709. doi: 10.1038/ncomms14709.
Neurons reprogramme encephalitogenic T cells (T) to regulatory T cells (T), either FoxP3T or FoxA1T. We reported previously that neuronal ability to generate FoxA1T was central to preventing neuroinflammation in experimental autoimmune encephalomyelitis (EAE). Mice lacking interferon (IFN)-β were defective in generating FoxA1T in the brain. Here we show that lack of neuronal IFNβ signalling is associated with the absence of programme death ligand-1 (PDL1), which prevents their ability to reprogramme T cells to FoxA1T. Passive transfer-EAE via IFNβ-competent T cells to mice lacking IFNβ and active induced-EAE in mice lacking its receptor, IFNAR, in the brain (Nes:Ifnar) result in defective FoxA1T generation and aggravated neuroinflammation. IFNβ activates neuronal PI3K/Akt signalling and Akt binds to transcription factor FoxA1 that translocates to the nucleus and induces PDL1. Conversely, inhibition of PI3K/Akt, FoxA1 and PDL1 blocked neuronal ability to generate FoxA1T. We characterize molecular factors central for neuronal ability to reprogramme pathogenic T cells to FoxA1T preventing neuroinflammation.
神经元将致脑炎 T 细胞（T）重编程为调节性 T 细胞（T），包括 FoxP3T 或 FoxA1T。我们之前报道过，神经元产生 FoxA1T 的能力对于预防实验性自身免疫性脑脊髓炎（EAE）中的神经炎症至关重要。缺乏干扰素（IFN）-β的小鼠在大脑中产生 FoxA1T 的能力存在缺陷。在这里，我们表明神经元 IFNβ 信号缺失与程序性死亡配体-1（PDL1）的缺失有关，这阻止了它们将 T 细胞重编程为 FoxA1T 的能力。通过 IFNβ 功能正常的 T 细胞向缺乏 IFNβ 的小鼠传递性 EAE，以及在缺乏其受体 IFNAR 的小鼠中诱导大脑中的 EAE（Nes：Ifnar），导致 FoxA1T 的产生缺陷和神经炎症加重。IFNβ 激活神经元 PI3K/Akt 信号通路，Akt 与转录因子 FoxA1 结合，FoxA1 易位到细胞核并诱导 PDL1。相反，抑制 PI3K/Akt、FoxA1 和 PDL1 会阻止神经元产生 FoxA1T 的能力。我们描述了神经元将致病性 T 细胞重编程为 FoxA1T 以预防神经炎症的核心分子因素。
