Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease
- PMID: 31915375
- PMCID: PMC7445078
- DOI: 10.1038/s41586-019-1895-7
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease
Abstract
Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. 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+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA 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+ TEMRA 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.
Conflict of interest statement
Competing interests
D.G., N.S., M.M.D. and T.W.-C. are co-inventors on a patent application related to this work. Patent STDU2–36496/US-1/PRO is for compositions and methods for measuring T cell markers associated with Alzheimer’s disease.
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Comment in
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An immune-cell signature marks the brain in Alzheimer's disease.Nature. 2020 Jan;577(7790):322-323. doi: 10.1038/d41586-019-03892-8. Nature. 2020. PMID: 31937952 No abstract available.
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T cells on patrol in Alzheimer disease.Nat Rev Neurol. 2020 Mar;16(3):128-129. doi: 10.1038/s41582-020-0317-7. Nat Rev Neurol. 2020. PMID: 31988485 No abstract available.
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T cells in Alzheimer's disease: space invaders.Lancet Neurol. 2020 Apr;19(4):285-287. doi: 10.1016/S1474-4422(20)30076-4. Epub 2020 Mar 18. Lancet Neurol. 2020. PMID: 32199089 No abstract available.
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Human herpesvirus 4 and adaptive immunity in Alzheimer's disease.Signal Transduct Target Ther. 2020 Apr 13;5(1):48. doi: 10.1038/s41392-020-0125-y. Signal Transduct Target Ther. 2020. PMID: 32296032 Free PMC article. No abstract available.
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