Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline
Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline
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DOI：
10.1038/s43587-021-00049-z
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发表时间：
2021-04-01
期刊：
影响因子：
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通讯作者：
Martini, Rudolf
中科院分区：
文献类型：
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作者：
Groh, Janos;Knoepper, Konrad;Martini, Rudolf
即使没有疾病或创伤，衰老也是神经系统功能衰退的主要危险因素。轴突髓磷脂单位和突触末梢是最容易受到衰老相关退化影响的一些神经结构(1-6)，但其潜在机制却知之甚少。在周围神经系统中，巨噬细胞（先天免疫系统的重要代表）是衰老过程中有髓纤维和运动终板结构和功能衰退的重要驱动因素 (7)。同样，在衰老的中枢神经系统 (CNS) 中，小胶质细胞会促进有髓轴突和突触的损伤 (8-20)。在这里，我们研究了细胞毒性 CD8(+) T 淋巴细胞的作用，这是一种适应性免疫细胞，之前被认为是各种遗传介导的 CNS 疾病模型中轴突扰动的放大器 (21)，但在衰老的 CNS22-25 中尚未得到充分研究。我们发现，CD8(+) T 细胞的积累会导致正常衰老小鼠中枢神经系统的轴突变性，并导致与年龄相关的认知和运动能力下降。我们通过单细胞转录组学描述了成年和老年小鼠大脑中 CD8(+) T 细胞群的异质性，并识别了与衰老相关的变化。从机制上讲，我们提供的证据表明 CD8+ T 细胞以 T 细胞受体和颗粒酶 B 依赖性方式驱动轴突变性。老年小鼠而非成年小鼠的全身炎症会进一步加剧细胞毒性神经损伤。我们还发现老年人白质尸检材料中 T 细胞的密度有所增加。我们的研究结果表明，针对老年人的 CD8(+) CNS 相关 T 细胞可能会减轻与衰老相关的大脑结构和功能衰退。
Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon-myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration(1-6), but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages-important representatives of the innate immune system-are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging(7). Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses(8-20). Here we examine the role of cytotoxic CD8(+) T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases(21) but understudied in the aging CNS22-25. We show that accumulation of CD8(+) T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8(+) T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8(+) T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8(+) CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function.