Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control¹. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS¹. Although several ALS-associated genes have been shown to affect immune functions², whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression³. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (T_EMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded T_EMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

肌萎缩侧索硬化症 (ALS) 是一种异源性神经退行性疾病，会影响运动神经元和随意肌控制¹。ALS 异质性包括表现年龄、进展速度和症状发作的解剖部位。特定基因中的致病突变已被确定并定义了 ALS ¹的不同亚型。尽管已证明几个 ALS 相关基因会影响免疫功能²，但对于特定免疫功能是否会导致 ALS 异质性，人们知之甚少。肌萎缩性侧索硬化症 4 (ALS4) 的特点是幼年发病且进展缓慢³. ALS4 患者在 30 多岁时表现出运动困难，其中大多数人在 50 多岁时需要辅助行走的设备。ALS4 是由 senataxin 基因 ( SETX ) 突变引起的。在这里，我们使用携带 ALS4 致病性 L389S 突变的Setx敲入小鼠，描述了一种免疫学特征，该特征由克隆扩增的、终末分化的效应记忆 (T _EMRA) 中枢神经系统和敲入小鼠血液中的 CD8 T 细胞。敲入小鼠中抗原特异性 CD8 T 细胞频率的增加反映了运动神经元疾病的进展并与抗神经胶质瘤免疫相关。此外，骨髓移植实验表明免疫系统在 ALS4 神经变性中起着关键作用。在患有 ALS4 的患者中，克隆扩增的 T _EMRA CD8 T 细胞在外周血中循环。我们的结果提供了 ALS4 中抗原特异性 CD8 T 细胞反应的证据，可用于揭示疾病机制并作为疾病状态的潜在生物标志物。