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

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.

Abstract

Aging is associated with the formation of focal white matter lesions and atrophy. The authors discovered a role for CD8 ⁺ T cells in driving white matter-specific interferon responses in microglia and oligodendrocytes, leading to oligodendrocyte loss.