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T cell Infiltration into the Neurogenic Niche Linked to Age-related Decline in Brain Function

Review of “Single-cell analysis reveals T cell infiltration in old neurogenic niches” from Nature by Stuart P. Atkinson

A decline in tissue function is one of the well-known hallmarks of aging, and recent research from the laboratory of Anne Brunet (Stanford University School of Medicine, Stanford, CA, USA) sought to explore how altered cell composition may affect overall tissue function. The neurogenic niche of the adult mouse subventricular zone displays alterations and functional decline over time at the single-cell level, and in their new Nature study, the team now establish a link between this decline and immune cell infiltration into the niche [1] and raise the possibility of counteracting the age-related decline in brain function.

Dulken et al. first analyzed the single-cell composition of the subventricular zone neurogenic niche in young (3-month old) and aged mice (nearly 30-month-old) via fluorescence-activated cell sorting combined with single-cell RNA sequencing. This analysis revealed a decrease in the number of activated neural stem cells (NSCs), changes to endothelial cells and microglia, and, most interestingly, the infiltration of T cells into the neurogenic niche in aged mice when compared to young mice.

With a focus on T cell infiltration, the authors established that the clonally-expanded T cells found in the aged neurogenic niche displayed differences when compared to T cells from the blood of aged mice, suggesting that they may recognize a specific antigen in the old brain. Of note, analyses of brains from elderly humans (none of which displaying overt signs of neurodegenerative disease) also revealed CD8+ T cells infiltration of the neurogenic region lining the lateral ventricle [2], leading the authors to conclude that the infiltration of T cells also occurs in the brains of aged humans.

Interestingly, niche-infiltrating T cells also expressed high levels of the inflammatory cytokine interferon-γ. Several cell types within the niche responded to T cell-secreted interferon-γ; however, NSCs displayed a high interferon response (as measured by the increase in the surface expression of the BST2 protein) that prompted a decrease proliferation, suggestive of a reduction in neurogenesis. The authors suggest that infiltrating T cells may recognize neoantigens, such as those from aggregated proteins in old NSCs [3], while other niche cells, such as microglia [4], endothelial cells [5], or macrophages [6], may secrete T cell attractive chemokines. 

Finally, the authors sought to confirm the inhibitory effect of interferon-γ-expressing T cells on NSCs. In vitro cocultures of interferon-γ-expressing T cells with young mouse NSCs led to reduced NSC proliferation, while the forced entry of CD8+ T cells into the brains of young mice led to an increase in the proportion of BST2-positive NSCs that displayed a reduced proliferative potential.

While the authors note that further research will be required to fully explain the link between T cells, interferon-γ, and NSC proliferation, their findings do highlight a possible mechanism behind the decline of neurogenic niche functionality during aging. Furthermore, they believe that this new mechanism will represent a new target for the development of therapies to effectively counteract the age-associated decline in brain function.

For more on how NSCs, neurogenesis, and how blocking immune cell infiltration and function in the neurogenic niche may represent an exciting new means to inhibit functional decline in the aged brain, stay tuned to the Stem Cells Portal!

References

  1. Dulken BW, Buckley MT, Navarro Negredo P, et al., Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 2019;571:205-210.
  2. Ernst A, Alkass K, Bernard S, et al., Neurogenesis in the Striatum of the Adult Human Brain. Cell 2014;156:1072-1083.
  3. Leeman DS, Hebestreit K, Ruetz T, et al., Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 2018;359:1277-1283.
  4. Salter MW and Stevens B, Microglia emerge as central players in brain disease. Nature Medicine 2017;23:1018.
  5. Pober JS and Sessa WC, Evolving functions of endothelial cells in inflammation. Nature Reviews Immunology 2007;7:803.
  6. Mrdjen D, Pavlovic A, Hartmann FJ, et al., High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity 2018;48:380-395.e6.