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. De 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. DavisTony Wyss-Coray

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)399-404
Number of pages6
JournalNature
Volume577
Issue number7790
DOIs
StatePublished - Jan 16 2020
Externally publishedYes

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    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., ... Wyss-Coray, T. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature, 577(7790), 399-404. https://doi.org/10.1038/s41586-019-1895-7