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Stress regulates Alzheimer's Disease progression via selective enrichment of CD8+ T cells

ABSTRACT: This study investigates stress's impact on Alzheimer's disease (AD) using male APP/PS1 transgenic mice. Negative stressors (chronic social defeat, restraint) and positive hedonia (environmental enrichment, EE) were applied. Stress worsens AD pathology, while EE slows progression. Brain RNA-seq reveals IL-6 and IL-10 as key stress-related AD regulators. Flow cytometry shows CD8+/CD4+ T cell ratio shifts in response to SE and EE. SE increases CD8+/CD4+ ratio, opposite in EE. Depletion and enrichment of CD8+ T cells both accelerate AD, indicating immune intervention's negative impact. Stress management and balanced immunity may aid AD therapy, highlighting novel potential treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE244131 | GEO | 2023/12/15

REPOSITORIES: GEO

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Project description:T cell receptor (TCR) αβ+ CD4- CD8- double negative T cells represent a rare T cell subset implicated in the pathogenesis of several autoimmune diseases. In this study, we investigated the DNA methylation signature of double negative T cells to gain insight into the epigenetic architecture and transcriptional capacity of peripheral blood primary human double negative T cells compared to autologous CD4+ and CD8+ T cells. We identified 2,984 CG sites across the genome with unique loss of DNA methylation in double negative T cells, and showed significant reduction in mRNA expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. DNA methylation was increased in CD8A/CD8B and CD4 consistent with epigenetic repression of both the CD8 and CD4 genetic loci in double negative T cells. Curiously, we show consistent increase in non-CG methylation in double negative T cells, a finding suggestive of pluripotency and previously only known to occur in embryonic stem cells and developing brain tissue. Network analyses of genes hypomethylated in double negative compared to CD4+ and CD8+ T cells indicate a strong relationship between double negative T cells and functions related to cell-cell interaction, cell adhesion, and cell activation pathways. Our data also suggest a robust pro-inflammatory epigenetic signature in double negative T cells, consistent with a transcriptional permissiveness to produce key inflammatory cytokines including IFNγ, IL-17F, IL-12B, IL-5, IL-18, TNFSF11 (RANKL), and TNFSF13B (BLYS or BAFF). These findings highlight an epigenetic basis for a role of double negative T cells in autoimmunity and extend the potential pathogenic transcriptional capacity of this unique T cell subset. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood samples of 7 unrelated healthy women (age range 25-60) (Supplementary Table 1) by Ficoll-gradient centrifugation (GE Healthcare Bio-Sciences AB, Uppsala, Sweden). Subsequently, T cells were negatively-selected using the Human Pan T Cell Isolation II kit (Miltenyi Biotec, Cambridge, MA). T cells were then analyzed and sorted into TCRαβ+ CD4+ T cells, TCRαβ+ CD8+ T cells, and TCRαβ+ DN T cell subsets by flow cytometry. DNA was isolated from CD4+, CD8+, and DN T cell subsets using the DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA), then bisulfite-converted using the EZ DNA Methylation kit (Zymo Research, Irvine, CA) for DNA methylation studies.

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Stress regulates Alzheimer's Disease progression via selective enrichment of CD8+ T cells

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