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Altered Immune Cell Activity Reported in Aging Mouse, Human Brains

NEW YORK – A team led by investigators at Stanford University has used single-cell transcriptomics to untangle changing brain and immune cell interactions in aging mouse brains.

"The textbooks say that immune cells can't easily get into the healthy brain, and that's largely true," senior and corresponding author Anne Brunet, a genetics and aging biology researcher at Stanford, said in a statement. "But we've shown that not only do they get into otherwise healthy aging brains — including human brains — but they reach the very part of the brain where new neurons arise."

The researchers did single-cell RNA sequencing on almost 14,700 individual cells obtained from neurogenic samples in young and old mice, garnering gene expression insights from up to 11 different cell types. In the nervous system samples from the older mice, for example, they saw declining number of activated neural stem cells, along with endothelial and microglia cell shifts.

On the immune cell side, aging appeared to coincide with enhanced T cell infiltration and T cell clonal expansions suspected of targeting antigens specifically found in the brain, but not in matched blood samples from the mice. A series of follow-up experiments suggested that interferon-gamma cytokines secreted by T cells in old mouse brains could staunch the proliferation of at least some neural stem cells.

"Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function," Brunet and her colleagues wrote in their study, published online today in Nature.

The researchers did 10x Genomics Chromium single-cell RNA-seq or nested PCR analyses on 14,685 cells from the adult subventricular zone in three-month-old ("young") mice and in three elderly mice that had reached nearly two-and-a-half years old. From markers in the resulting cell clusters, they identified 11 cell types, ranging from astrocytes and activated neural stem cells to microglia, macrophages, and more.

T cells appeared to be more profuse, infiltration-prone, and clonally expanded in neurogenic samples from the old mice — results supported by their additional immunofluorescence staining, fluorescence activated cell sorting, and T cell receptor sequence analyses.

"We did find an extremely sparse population of killer T cells in the subventricular zone of young mice," Brunet said in a statement. "But in the older mice, their numbers were expanded by 16-fold."

Such findings seemed to line up with CD8+ T cell infiltration patterns that the team identified in elderly human brains when it analyzed samples obtained at autopsy from five individuals between the ages of 20 and 44 and six individuals between 79 and 93 years old.

When the researchers focused on the expression and effects of T cell interferon-gamma, meanwhile, they found that older neural stem cells with enhanced expression of a cell surface marker called BST2 appeared particularly apt to respond to that cytokine, leading to diminishing proliferation of these cells. 

"Although the exact link between T cells, interferon, and [neural stem cell] proliferation remains to be established," the authors concluded, "our results provide a possible cause for the decline of [neural stem cells] during aging and suggest avenues through which to counteract age-associated cognitive impairment."