Nature
Infiltration of old brains by T cells causes dysfunction of neural stem cells.

In a healthy adult, tissue-specific stem cells replenish damaged tissue and sustain plasticity - the addition of new cells - in organs. In two regions of the adult brains of most mammals - the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus, neural stem cells generate new neurons, which contribute to brain plasticity and cognition. However, there is still debate over whether new neurons are commonly generated in the adult human brain. The proliferation of neural stem cells in mammals decreases with age, resulting in a reduction in the number of new neurons formed over time, and the mechanism underlying this change is poorly understood. Writing in Nature, Dulken and others examined how changes in the microenvironment of neural stem cells in the brains of old mice affect stem-cell proliferation.

Stem cells in an old brain are dysfunctional and are less likely to divide than are young stem cells. However, the intrinsic properties of neural stem cells remain stable - both young and old neural stem cells have a similar potential to differentiate and proliferate in vitro5. Stem cells are located in a specialized microenvironment called a niche, which consists of molecules and other cells that interact with stem cells to support their division, survival and function. Age-associated changes in the neural-stem-cell microenvironment have not been well characterized. Thus, an unanswered question is whether changes in this microenvironment might drive age-related stem-cell dysfunction.

Dulken and others investigated how ageing affects different cell types in the neural-stem-cell niche in the subventricular zone of the adult mouse brain. The authors used a technique called single-cell ribonucleic acid sequencing to examine gene expression in individual cells in this niche in young and old mice. They observed genome-wide differences between the young and old animals in the gene-expression patterns of endothelial cells and of cells called microglia and oligodendrocytes.

The authors also observed that immune cells called T cells - specifically, a class of T cell that expresses the protein CD8 - were present in old but not young brains. Imageing analysis revealed that these T cells were in close proximity to neural stem cells. The authors also found that, in old human brains, T cells infiltrated an area that is equivalent to the region of the mouse brain that was infiltrated by T cells. These findings raise the possibility that T cells affect ageing stem cells. This discovery is intriguing because a healthy brain is surrounded by a boundary called the blood-brain barrier, which tightly regulates what can enter the brain, and immune cells in the bloodstream do not normally cross this barrier.

The authors found that, compared with T cells in the bloodstream, T cells in the ageing mouse brain make higher levels of a protein called interferon-y, which is a type of immune signalling molecule called a cytokine. Cytokine production is a hallmark of T cells that have become activated, which occurs when they recognize a fragment of a protein called an antigen. Dulken and colleagues report that neural stem cells express the receptor for interferon-y, which suggests that interferon-y might be used for signalling between T cells and neural stem cells. When analysed using single-cell ribonucleic acid sequencing, a subpopulation of the old neural stem cells was found to express exceptionally high levels of genes that are expressed in response to interferon-y signalling. And when the authors monitored the ability of these high-responding cells to divide in vivo, they found that the cells proliferated less than did the neural stem cells that had a low response to interferon-y in vivo.

To test the hypothesis that interferon-y can decrease the proliferation of neural stem cells, Dulken and colleagues used a technique that enabled T cells to enter the brains of young mice. This T-cell influx was accompanied by an increase in the interferon-y response of neural stem cells and a decrease in their proliferation. The authors also cultured neural stem cells from young mice in vitro in the presence or absence of T cells. When cytokines that induce T-cell secretion of interferon-y were added to these cultures, the neural stem cells co-cultured with T cells proliferated less than did those cultured in the absence of T cells. The impaired proliferation in the presence of T cells could be prevented by an antibody that blocked interferon-y signalling. Dulken and colleagues work is consistent with a model suggesting that the microenvironment of neural stem cells in the aged brain is infiltrated by T cells that release interferon-y, which is sufficient to inhibit neural-stem-cell proliferation.

The authors evidence for the previously unsuspected infiltration of T cells into an aged brain raises the question of what mechanism is responsible for this invasion, and whether signals in the ageing brain might recruit T cells to the brain. Future studies should determine which antigens the infiltrating T cells recognize. T cells that express the protein CD4 in the bloodstream outside the brain have a role in regulating the formation of new neurons in the young dentate gyrus through an unknown mechanism, and it would be interesting to learn whether T cells that express CD8 infiltrate the old dentate gyrus to inhibit stem-cell proliferation. Would blocking interferon-y in the aged brain increase stem-cell proliferation and the generation of new neurons, and would this also improve cognition? Many such fascinating questions remain to be investigated.

Dulken and colleagues work adds to a growing body of evidence that points to interactions between immune cells and stem cells as a cause of age-related decline in tissue function. Perhaps therapies can be developed to target the immune system as a way of combating ageing-related stem-cell deficits throughout the body.