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

David Gate (), Naresha Saligrama, Olivia Leventhal, Andrew C. Yang, Michael S. Unger, Jinte Middeldorp, Kelly Chen, Benoit Lehallier, Divya Channappa, Mark B. Los Santos, Alisha McBride, John Pluvinage, Fanny Elahi, Grace Kyin-Ye Tam, Yongha Kim, Michael Greicius, Anthony D. Wagner, Ludwig Aigner, Douglas R. Galasko, Mark M. Davis and Tony Wyss-Coray ()
Additional contact information
David Gate: Stanford University School of Medicine
Naresha Saligrama: Stanford University
Olivia Leventhal: Stanford University School of Medicine
Andrew C. Yang: Stanford University
Michael S. Unger: Paracelsus Medical University
Jinte Middeldorp: Stanford University School of Medicine
Kelly Chen: Stanford University School of Medicine
Benoit Lehallier: Stanford University School of Medicine
Divya Channappa: Stanford University School of Medicine
Mark B. Los Santos: Stanford University School of Medicine
Alisha McBride: Stanford University School of Medicine
John Pluvinage: Stanford University School of Medicine
Fanny Elahi: University of California at San Francisco
Grace Kyin-Ye Tam: Stanford University School of Medicine
Yongha Kim: Stanford University School of Medicine
Michael Greicius: Stanford University School of Medicine
Anthony D. Wagner: Stanford University
Ludwig Aigner: Paracelsus Medical University
Douglas R. Galasko: University of California at San Diego
Mark M. Davis: Stanford University
Tony Wyss-Coray: Stanford University School of Medicine

Nature, 2020, vol. 577, issue 7790, 399-404

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-019-1895-7

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