O4-09-06: clonally expanded cd8 t cells patrol alzheimer's cerebrospinal fluid

Alzheimer's disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation is increasingly recognized to play a critical function. While innate inflammation has been implicated in AD, little is known about the contribution of the adaptive immune response. Here we performed mass cytometry of peripheral blood mononuclear cells combined with unbiased discovery and machine learning techniques and found an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. We then used single cell T cell receptor (TCR) sequencing to detect and phenotype these cells in the cerebrospinal fluid (CSF) Levels of the brain homing chemokine C-X-C motif ligand 9 (CXCL9) were significantly higher in AD patient plasma and peripheral CD8+ T cell numbers were strongly associated with cognition. Strikingly, we discovered CD8+ TEMRA cells were also present in patient CSF and TCR sequencing indicated their clonal expansion, suggesting antigen specificity of these adaptive immune cells. These results reveal a novel blood-CSF adaptive immune response in AD and provide the first evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration. Furthermore, we present TCR sequencing of individual CSF T cells as a novel, non-invasive method to pursue biomarkers of neurodegeneration.