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CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.

Nat Neurosci. 2022 Nov;25(11):1446-1457. doi: 10.1038/s41593-022-01183-6. Epub 2022 Oct 24. PMID: 36280798; PMCID: PMC9630119.

Authors/Editors: Kaya T, Mattugini N, Liu L, Ji H, Cantuti-Castelvetri L, Wu J, Schifferer M, Groh J, Martini R, Besson-Girard S, Kaji S, Liesz A, Gokce O, Simons M.
Publication Date: 2022

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Abstract

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8+ T cells in aging white matter. In summary, we provide evidence that CD8+ T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

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