Transcriptomic profiling identifies CD8+ T-cells in the brain of aged and Alzheimer’s disease transgenic mice as tissue-resident memory T-cells

Immune cell infiltration to the brain is a prominent feature in aging and in various neurodegenerative diseases such as Alzheimer´s disease (AD). For example, a specific subpopulation of CD8+ T-cells clonally expands in the CSF of AD patients. Also, with AD progression that typically includes amyloid-beta plaque formation, neuronal damage and microglia-associated neuroinflammation, CD8+ T-cells infiltrate into the AD brain parenchyma and tightly associate with neuronal and microglia structures. The functional properties of CD8+ T-cells in the brain are largely unknown, besides the fact that experimental ablation in a transgenic AD animal model (APP-PS1) leads to changes in the expression of neuronal- and synapse-related genes. To gain further insights into the putative functional role of CD8+ T-cells in the brain, we explored and compared the transcriptomic profile of these cells in blood and brain of aged and transgenic AD mice. Surprisingly, CD8+ T-cells isolated from brains of aged APP-PS1 and WT animals had a similar transcriptomic profile, but they substantially differed from blood circulating CD8+ T-cells. The gene expression signature of brain CD8+ T-cells from APP-PS1 mice identified these cells as tissue-resident memory T-cells (Trm) indicated by specific regulation of genes such as Klf2/3, Ccr7, Sell, and Cxcr6. Immunohistochemical analysis confirmed the Trm identity of CD8+ T-cells at sites of amyloid-plaques. Gene ontology enrichment analysis on the significantly up-regulated genes showed an overrepresentation of biological processes as “response to virus”, “T-cell mediated immunity” and “response to interferon-beta” suggesting similarities to virus-responding T-cells. This is also supported by KEGG analysis, which highlighted upregulation of several pathways for “virus infections”, “cellular senescence” and “antigen processing and presentation”. In addition, the transcriptome of APP-PS1 brain CD8+ T-cells overlapped with gene microarray data of brain Trm CD8+ T-cells derived from an acute virus infection mouse model, suggesting similar functions of CD8+ T-cells in the brain either after viral infections or in AD. In conclusion, our herein presented data give new insights on the transcriptome of brain CD8+ T-cells and demonstrate adaptive immune responses in transgenic AD mice. This might open the door for immunotherapy as potential treatment option for AD. Two different strains were used: Seven APP Swedish PS1 dE9 (APP-PS1) mice and ten wild type (WT) mice. Whole transcriptome analysis of CD8+ T-cells in blood and brain was compared between aged and transgenic AD mice and wild type strain