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Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease
Author(s) -
Gate David,
Saligrama Naresha,
Levanthal Olivia,
Davis Mark,
WyssCoray Tony
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044082
Subject(s) - immunology , immune system , cytotoxic t cell , t cell receptor , cd8 , biology , acquired immune system , t cell , mass cytometry , phenotype , gene , genetics , in vitro
Abstract Background Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD. Method First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8 + T effector memory CD45RA + (T EMRA ) cells. Result In a second cohort, we found that CD8 + T EMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8 + T EMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein‐Barr virus antigens. Conclusion These results reveal a novel blood‐CSF adaptive immune response in AD and provide evidence of clonal, antigen‐experienced T cells patrolling the intrathecal space of brains affected by age‐related neurodegeneration.