A novel blood-CSF adaptive immune response in Alzheimer's disease

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. Preliminary data featured in this application demonstrate a peripheral immune signature of AD characterized by increased numbers of highly-differentiated CD8+ T effector memory CD45RA+ (TEMRA) cells. Strikingly, CD8+ TEMRA cells were also present in patient cerebrospinal fluid (CSF) and T cell receptor (TCR) sequencing indicated their clonal expansion, suggesting antigen specificity of these adaptive immune cells. TCR cloning and peptide screens demonstrated specificity of a subset of clonally expanded AD CSF TCRs to the Epstein-Barr virus (EBV) BZLF1 antigen. These results provide the first evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration. This K99/R00 application will test the novel theory of a detrimental adaptive immune response contributing to AD pathobiology. During the K99 portion of this grant, AD blood-CSF T cell clonotypes were identified. This approach determined specific T cell populations in AD. In the R00 portion of the grant, antigen identification screens will be used to detect the self/non-self antigen(s) driving T cell clonal expansion in AD, as was proposed in Specific Aim 2. These assays could uncover a novel therapeutic target or biomarker for AD. Additionally, experiments are underway for Specific Aim 3, which will determine mechanisms of T cellmediated neuronal death and resiliency in AD using induced neuronal (iN) cells co-cultured with patient CSF CD8+ T cells. These experiments will assess whether AD CSF CD8+ T cells mount cytotoxic effector responses to iN cells infected with EBV and/or to a molecular mimic of BZLF1. The candidate, Dr. David Gate, has established a research lab in the Neurology department at Northwestern University as of September 1, 2021. Dr. Gate has extensive experience in T cell biology and has spent more than a decade studying AD. During the K99 mentoring phase of this award, Dr. Gate advanced his knowledge in next-generation sequencing analysis, sophisticated statistical methods, antigen screening, iN culturing methods and CRISPR gene editing. As an independent investigator, Dr. Gate will leverage the training under this fellowship to comprehensively and quantitatively evaluate the interactions between T cell molecular components and neurodegeneration.