Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease

Nature, 2020 · DOI: 10.1038/s41586-019-1895-7 · Published: January 1, 2020

Simple Explanation

Alzheimer's disease (AD) is characterized by neuroinflammation, and this study investigates the role of the adaptive immune system, particularly T cells, in AD. The study found increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells in the blood of AD patients, which were negatively associated with cognition. The researchers discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid (CSF) of AD patients, indicating an adaptive immune response in the brain. These T cells were found to be specific to Epstein-Barr virus (EBV) antigens, suggesting a potential link between viral infections and AD. Overall, the study provides evidence that clonal, antigen-experienced T cells patrol the intrathecal space of brains affected by age-related neurodegeneration, suggesting a potential role for adaptive immunity in the progression of AD.

Study Duration

Not specified

Participants

164 living subjects (97 healthy, 31 MCI, 28 AD, 8 PD) and post-mortem brains from control individuals and patients with AD

Evidence Level

Not specified

Key Findings

1
Increased numbers of CD8+ TEMRA cells were found in the peripheral blood of patients with MCI or AD, and these cells were negatively associated with cognition.
2
Clonally expanded CD8+ TEMRA cells were discovered in the cerebrospinal fluid of patients with Alzheimer’s disease.
3
The clonally expanded TCRs in the CSF of AD patients showed specificity to two separate Epstein-Barr virus antigens.

Research Summary

This study investigates the role of adaptive immunity in Alzheimer's disease (AD) by analyzing peripheral blood and cerebrospinal fluid (CSF) samples from healthy individuals, patients with mild cognitive impairment (MCI), AD, and Parkinson's disease (PD). The researchers found an increased population of CD8+ TEMRA cells in the peripheral blood of AD patients, which correlated negatively with cognitive function. Single-cell RNA sequencing revealed enhanced T cell receptor (TCR) signaling in these cells. Clonal expansion of CD8+ TEMRA cells was observed in the CSF of AD patients, with specificity to Epstein-Barr virus (EBV) antigens, suggesting a potential link between adaptive immunity and viral infections in AD pathogenesis.

Practical Implications

Diagnostic potential

The identified immune signature of increased CD8+ TEMRA cells in peripheral blood could potentially serve as a diagnostic marker for AD.

Therapeutic targets

Understanding the role of antigen-specific T cells in AD could lead to new therapeutic strategies targeting the adaptive immune response.

EBV and AD link

Further research is needed to explore the potential causal link between EBV infection and the development or progression of AD.

Study Limitations

1
The study acknowledges that detecting EBV-specific TCRs in CSF from patients with AD is not evidence of a causal link between EBV infectivity and AD.
2
The most highly expanded clones observed in patient CSF may be specific for non-self antigens that were not identified in the search.
3
It is not clear whether cells enter the brain parenchyma via the CSF.

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