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Clonally expanded CD8 T cells patrol Alzheimer's cerebrospinal fluid [TEMRA]

ABSTRACT: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuroinflammation plays a critical function. Recurring viral infections and loss of immune competence increase risk for developing AD, yet the cellular and molecular mechanisms driving these immune changes are unknown. Here we performed mass cytometry of peripheral blood mononuclear cells and detected an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. CD8+ TEMRA cells were negatively associated with cognition and single cell RNA sequencing revealed their cytotoxic effector function. Strikingly, we discovered identical, shared T cell receptors (TCRs) of clonally expanded CD8+ TEMRA cells in cerebrospinal fluid (CSF) of three AD patients. Deep TCR sequencing, machine learning, and peptide screens identified the HLA-B*08:01-restricted Epstein-Barr virus trans-activator protein BZLF1 as the cognate antigen of a novel AD CSF TCR . These results provide the first evidence of clonal, antigen-specific T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration

ORGANISM(S): Homo sapiens

PROVIDER: GSE134576 | GEO | 2019/11/04

REPOSITORIES: GEO

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Project description:The goal of this study is to compare the transcriptional program and the TCR sequences of different subsets of CD8 T cells purified from the peripheral blood of 3 patienst with Amyotrophic Lateral Sclerosis 4 (ALS4) and 3 age-matched controls (unreleated). Peripheral blood mononuclear cells (PBMCs) were purified from 3 ALS4 patients and 3 age-matched healthy controls.By combining RNA and surface protein expression followed by multidimensional reduction using the Uniform Manifold Approximation and Projection (UMAP), we could identified 9 clusters corresponding to different CD8 T cell subsets: naïve/naïve like (clusters 0, 2, 5, 8), central memory (cluster 7), effector memory (clusters 4 and 6), TEMRA (clusters 1 and 3), and mucosal associated invariant T (MAIT) cells (cluster 9). ALS4 patients exhibited a higher proportion of TEMRA, and a decreased frequency of effector/effector memory cells, as compared to controls. Downregulation of IL7R and CCR7, and upregulation of GZMM and GZMB (encoding for Granzyme M and B, respectively), KLRB1 (Killer Cell Lectin Like Receptor B1), NKG7 (Natural Killer Cell Granule Protein 7), FGFBP2 (Fibroblast Growth Factor Binding Protein 2) and CCL4 (Chemokine (C-C motif) ligands 4), all of which correlate with a TEMRA phenotype are among the top deregulated genes in ALS4 CD8 T cells. The proportion of naïve cells seemed to be increased as well; however only 1 patient has an abnormal high frequency of CCR7+CD45RA+CD28+ cells, while the TEMRA signature was consistent among all 3 ALS4 donors. More than 90% of expanded clones (≥5) are TEMRA cells in ALS4 patients, in comparison to ~ 60% in healthy controls. By matching UMAP coordinates from RNA and TCR analyses, we observed a colocalization between the most expanded clones, i.e. CD8 T cells in which the same TCR sequence was shared by more than 20 cells, and the TEMRA subset that we found enriched in patients. We quantified this clonal expansion and found that over half of all TEMRA cells comprised of highly expanded clones in patients. Hyperexpanded (>100 clones) TEMRA cells were detected in 2 of the 3 patients, with one clone reaching as high as 407 cells. No hyperexpanded clones were found in other CD8 T cell subsets or in control patients. Comparison of surface protein expression from our CITE-seq analysis in “Low” and “High” (>20) expanded clones from ALS4 patients revealed a stronger TEMRA phenotype in the latter, as indicated by CD27 downregulation and CD45RA and CD57 upregulation.

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Clonally expanded CD8 T cells patrol Alzheimer's cerebrospinal fluid [TEMRA]

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