Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons
Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons
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DOI：
10.1073/pnas.1815961116
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发表时间：
2019-02-05
影响因子：
11.1
通讯作者：
Raoul, Cedric
中科院分区：
文献类型：
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作者：
Coque, Emmanuelle;Salsac, Celine;Raoul, Cedric
适应性免疫反应是肌萎缩性侧索硬化症（ALS）患者运动神经元丢失的动态变化的一部分。在神经退行性过程中调节保护性免疫的CD4(+) T细胞受到了最多的关注。CD8(+) T细胞也在患者和ALS小鼠的脊髓中被观察到，尽管它们对疾病的贡献仍然难以捉摸。在这里，我们发现活化的CD8(+) T淋巴细胞浸润中枢神经系统（CNS）在症状期的ALS小鼠模型。选择性消融表达als相关超氧化物歧化酶-1 (SOD1)（G93A）突变体的小鼠的CD8(+) T细胞可减少脊髓运动神经元的损失。使用运动神经元-CD8(+) T细胞共培养系统，我们发现表达CD8（+）的突变sod1 T淋巴细胞选择性地杀死运动神经元。这种细胞毒性活性需要识别肽-MHC-I复合体（其中MHC-I代表主要组织相容性复合体I类）。基于原子力显微镜的单细胞力谱测量相互作用强度表明，运动神经元与SOD1(G93A) CD8(+) T细胞之间存在特定的mhc - i依赖性相互作用。激活突变体SOD1 CD8(+) T细胞产生干扰素- γ，引起运动神经元中MHC-I复合物的表达，并通过Fas和颗粒酶途径发挥其细胞毒功能。此外，通过对ALS小鼠外周和中枢神经系统CD8(+) T细胞克隆多样性的分析，确定了中枢神经系统中CD8(+) T细胞受体的抗原限制性库。我们的研究结果表明，自我导向的免疫反应在疾病过程中发生，有助于选择性消除ALS中一部分运动神经元。
Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4(+) T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8(+) T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8(+) T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8(+) T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1)(G93A) mutant decreased spinal motoneuron loss. Using motoneuron-CD8(+) T cell coculture systems, we found that mutant SOD1-expressing CD8(+) T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1(G93A) CD8(+) T cells. Activated mutant SOD1 CD8(+) T cells produce interferon-gamma, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8(+) T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.