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Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function 1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease 2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (T EMRA) cells. In a second cohort, we found that CD8+ T EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ T EMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.
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“T-lymphocyte infiltration into the brain has been previously reported in AD patients and has been associated with impaired cognition (Gate et al., 2020; Jorfi et al., 2023).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Gate et al., 2020
Experimental — accuracy not yet measuredIn the citing paper
“Dysfunctional meninges also represent an important contributor to neuroinflammation in neurodegenerative diseases by acting as a checkpoint for T-cell infiltration.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [686]
In the citing paper
“Finally, the systemic chronic inflammation resulting from immunosenescence and non-neurotropic viral infection compels immune cells in the peripheral blood to penetrate the blood-brain barrier (BBB) and choroid plexus and enter the brain,345,346 Additionally, immune cells originating from the cranial bone marrow migrate to the meninges,347 thereby promoting neuroinflammation and neuronal”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [348]
In the citing paper
“Indeed, increased clonal expansion and CD8+ T cell infiltration in the brain are observed both in AD patients and during aging (48, 49).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [48]
In the citing paper
“Interestingly, several recent studies suggest that AD is associated with viral infection (47, 48).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [48]
In the citing paper
“The infiltration of clonally expanded T cells and B cells is also observed in the brain and other tissues with ageing in mice and humans69,71–73, and it is accentuated in age-related diseases74,75.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [74]
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Metadata
- Authors
- Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., Chen, K., Lehallier, B., Channappa, D., De Los Santos, M. B., McBride, A., Pluvinage, J., Elahi, F., Tam, G. K.-Y., Kim, Y., Greicius, M., Wagner, A. D., Aigner, L., Galasko, D. R., Davis, M. M., & Wyss-Coray, T.
- Affiliations
- VA Palo Alto Health Care System (US)
- Stanford Medicine (US)
- Stanford University (US)
- Paracelsus Medical University (AT)
- Utrecht University (NL)
- University of California, San Francisco (US)
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gate, David
- ORCID
- Venue
- Nature
- Published
- 2020-01-08
- Volume
- 577
- Issue
- 7790
- Pages
- 399-404
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7445078
- OpenAlex
- W3000319248
- Cited by
- 992
- References
- 32
- Citations by year
- 2026: 158 · 2025: 161 · 2024: 160 · 2023: 166 · 2022: 149 · 2021: 129 · 2020: 66
- FWCI
- 50.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs
- Cure Alzheimer's Fund
- Multiple Sclerosis Society
- NOMIS Stiftung
- National Institutes of Health (AI057229)
- National Institute on Aging (F32AG055255, AG055255-01A1, P50AG047366, AG045034, R01 AG045034 05, R01AG045034, R01AG048076, K24AG045333, P01AG019724, P30AG062422, P30AG066515, T32AG023481)
- National Institute of Allergy and Infectious Diseases (U19AI057229)
- National Institute of Neurological Disorders and Stroke (R00NS112458, K99NS112458)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Alzheimer's disease, CD8+ T cells, TEMRA cells, cerebrospinal fluid, T cell clonal expansion, T cell receptor repertoire, adaptive immune response, neuroinflammation, age-related neurodegeneration, cognitive decline
- MeSH terms
- Aged, Alzheimer Disease, Amino Acid Sequence, Cerebrospinal Fluid, Humans, Immunologic Memory, Middle Aged, Receptors, Antigen, T-Cell, Cohort Studies, CD8-Positive T-Lymphocytes, Sequence Analysis, Protein
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