Neurons are MHC class I-dependent targets for CD8 T cells upon neurotropic viral infection.
Neurons are MHC class I-dependent targets for CD8 T cells upon neurotropic viral infection.
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DOI：
10.1371/journal.ppat.1002393
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发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Gonzalez-Dunia D
中科院分区：
文献类型：
--
作者：
Chevalier G;Suberbielle E;Monnet C;Duplan V;Martin-Blondel G;Farrugia F;Le Masson G;Liblau R;Gonzalez-Dunia D
在中枢神经系统（CNS）感染后，免疫系统面临着消除病原体而不对更新能力有限的神经元造成显著损伤的挑战。特别是，它被认为是保护神经元免受细胞毒性T淋巴细胞（CTL）的直接攻击，因为它们不表达主要组织相容性I类（MHC I）分子，至少在稳态。迄今为止，我们目前对神经元-CTL相互作用的具体情况的了解大多是基于人工诱导神经元上的MHC I表达，用外源肽加载它们并应用CTL克隆或细胞系的研究，这些克隆或细胞系通常在培养中分化。因此，关于在自然疾病过程中受感染的神经元和抗病毒CD 8 T细胞之间的相互作用的方式，还有很多东西有待发现。在此，我们使用嗜神经性博尔纳病病毒（BDV）引起的神经炎症模型，其中病毒特异性CTL已被证明是引发疾病的主要免疫效应物。我们测试了脑分离的CD 8 T细胞对感染BDV的纯神经元培养物的致病特性。我们观察到，BDV感染的皮质神经元引发了显着的上调MHC I分子，使他们容易识别的抗病毒CTL，新鲜分离的急性感染大鼠的大脑。使用实时成像，我们分析了神经元和CTL之间的时空关系。脑分离的CTL表现出降低的流动性，并建立了稳定的接触与BDV感染的神经元，在抗原和MHC依赖的方式。这种相互作用引起神经元的快速形态变化，而不会立即杀死或损害电活动。神经元凋亡的早期迹象仅在最初接触后几小时就被检测到。因此，我们的研究结果表明，受感染的神经元可以有效地识别脑分离的抗病毒CD 8 T细胞，并揭示不寻常的形式CTL诱导的神经元损伤。当病毒感染大脑时，重要的是快速阻止病毒复制，而不会对神经元造成过度损伤，这些神经元不容易更新。细胞毒性T淋巴细胞（CTL）是清除病毒的主要因素之一。然而，CTL是否真的能够破坏受感染的神经元的问题仍然存在争议。在这项工作中，我们分析了感染的神经元和CTL之间的相互作用的特点，使用嗜神经性博尔纳病病毒（BDV）。这种病毒感染神经元并引发大脑严重炎症。我们直接从感染BDV的大鼠脑中分离CTL，并分析它们与原代神经元培养物的相互作用。使用活细胞荧光显微镜，我们观察到，CTL被逮捕后，遇到感染的神经元，他们建立了稳定的接触。此后，受感染的神经元表现出渗透性的快速变化，但在最终被破坏之前，仍保持存活和电活性数小时。我们的研究表明，神经元确实可以被CTL识别，这是一个重要的观察结果，有助于更好地了解病毒诱导的脑炎症的病理生理学。此外，它揭示了神经元对CTL诱导的杀伤具有相对抗性，这可能为新的治疗方法打开了机会之窗。
Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage. When a virus infects the brain, it is important to quickly block viral replication without causing excessive damage to neurons, which are not easily renewed. Cytotoxic T lymphocytes (CTL) are one of the main actors for virus elimination. However, the question of whether CTL are indeed capable of destroying infected neurons remains controversial. For this work, we analyzed the characteristics of interactions between infected neurons and CTL using neurotropic Borna disease virus (BDV). This virus infects neurons and triggers severe inflammation in the brain. We isolated CTL directly from the brains of rats infected with BDV and analyzed their interaction with primary cultures of neurons. Using live-cell fluorescence microscopy, we observed that CTL were arrested upon encounter with infected neurons and that they established stable contacts with them. Thereafter, infected neurons exhibited rapid changes in permeability but remained alive and electrically active for several hours, before ultimately being destroyed. Our study shows that neurons can indeed be recognized by CTL, an important observation for a better understanding of the physiopathology of virus-induced brain inflammation. In addition, it reveals that neurons are relatively resistant to CTL-induced killing, which may open a window of opportunity for new treatments.
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DOI：
10.1126/science.1164164
发表时间：
2008-10-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Knickelbein JE;Khanna KM;Yee MB;Baty CJ;Kinchington PR;Hendricks RL
通讯作者：
Hendricks RL
DOI：
10.1073/pnas.0602460103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Delhaye, Sophie;Paul, Sophie;Michiels, Thomas
通讯作者：
Michiels, Thomas
影响因子：
4.2
作者：
Chakraborty S;Nazmi A;Dutta K;Basu A
通讯作者：
Basu A
影响因子：
5.4
作者：
Guerin, JL;Gelfi, J;Messud-Petit, F
通讯作者：
Messud-Petit, F
影响因子：
32.4
作者：
Liblau, RS;Wong, FS;Santamaria, P
通讯作者：
Santamaria, P