Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline

Groh, Janos; Knöpper, Konrad; Arampatzi, Panagiota; Yuan, Xidi; Lößlein, Lena; Kastenmüller, Wolfgang; Martini, Rudolf

doi:10.1038/s43587-021-00049-z

Cited by 62 publications

(67 citation statements)

References 66 publications

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“…Brain aging is accompanied by T cell accumulation [ 1 – 3 ]. The infiltrated T cells and their secreted cytokines lead to a loss of functional neural stem cells in the subventricular zone (SVZ) [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

et al. 2022

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Background The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear. Results Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8+ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly. Conclusions Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

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Section: Introductionmentioning

confidence: 99%

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

et al. 2022

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“…CD8+ T cells have been shown to be involved in the pathophysiology of diseases associated with neurodegeneration. CD8+ T cells drive CNS axonal degeneration in normal senescent mice in a T cell receptor- and granzyme B-dependent manner, and this deleterious effect is further enhanced in the presence of inflammation (Groh et al, 2021 ). In addition, Coque et al ( 2019 ) found that autoreactive CD8+ T cells directly interacted with motor neurons and triggered death.…”

Section: The Peripheral Immune Systemmentioning

confidence: 99%

The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases

Zang

Chen

Zhu

et al. 2022

Front. Aging Neurosci.

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For decades, it has been widely believed that the blood–brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.

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“…Increased T cell invasion into the sub-ventricular zone of older brains was reported, along with the emergence of a reactive microglia subset as well as modified composition of BAM and DC subsets in geriatric mice ( Mrdjen et al, 2018 ; Dulken et al, 2019 ). CD8 T cell accumulation in the brain was shown to impair neurogenesis, drive axon degeneration, and contribute to cognitive and motor decline ( Dulken et al, 2019 ; Groh et al, 2021 ).…”

Section: Central Nervous System-immune Interactions During Aging and Neurodegenerationmentioning

confidence: 99%

Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases

Rickenbach

Gericke

2022

Front. Neurosci.

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The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options.

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Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline

Cited by 62 publications

References 66 publications

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases

Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases

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