T cells in the aging brain

SUMMARY
The overarching goal of this project is to understand how immune cells impact the brain during aging, with the
objective of restoring old brain function. The brain has long been considered an ‘immuno-privileged organ’.
However, recent studies have shown that immune cells infiltrate the brain in neurodegenerative diseases such
as Alzheimer’s disease and during aging. A key remaining challenge is to understand how immune cells impact
the brain during aging, and could this knowledge be used to restore functionality of old brain and treat
neurodegenerative diseases?
The subventricular zone (SVZ) of the adult brain provides a great paradigm to address this question, as this
regenerative region of the brain contains many different cell types – neural stem cells (NSCs), endothelial cells,
microglia – and exhibits clear functional decline during aging. To gain a single cell understanding of the changes
that occur with age in neurogenic niches, we recently performed single cell RNA-sequencing of young and old
neurogenic niches in mice. This analysis revealed a striking infiltration of cytotoxic T cells only in the old
neurogenic niche, which was confirmed by immunofluorescence. Surprisingly, we found that T cells from old
SVZs are clonally expanded and secrete interferon g (IFNg), suggesting that they have encountered specific
antigens. We also showed that T cells can impair NSC proliferation both in co-cultures and in vivo. Based on
these data, our specific hypothesis is that T cell clonal expansion in old brains drives the deterioration of the
neurogenic niche with age, and that preventing this T cell expansion restores function to old neurogenic regions.
Probing this idea would be critical to counter the decline in brain function during aging and neurodegenerative
diseases, such as Alzheimer’s disease. To test our hypothesis, we propose the following experiments:
1. To determine how T cells infiltrate neurogenic niches in old individuals;
2. To understand the functional impact of T cells on old neurogenic niches;
3. To examine the interaction between immune cells and neurogenic niches in young, old, and rejuvenated
individuals.
Completion of these aims will provide unique mechanistic insights into the regulation of T cell and other
immune cells during aging in regenerative niches of the brain. This work should also give a fundamental
understanding of the mechanistic impact of the interferon response and T cell cytotoxicity on different cell types
in the brain. Knowledge from our study should pave the way for building transformative strategies, including
new immunotherapies, for the restoration of a pristine tissue, which will be a critical step for improving brain
function during aging and age-related diseases such as Alzheimer’s disease.

Grant Number: 5R01AG071711-05
NIH Institute/Center: NIH
Principal Investigator: ANNE BRUNET