Cytotoxic CNS-associated T cells drive axon degeneration during aging.

Aging is known to be a major risk factor for perturbation of the nervous system even in the absence of distinct diseases or trauma. Current hypotheses postulate that axon-myelin units and synaptic terminals appear to be the structures most vulnerable to aging-related disintegration, but the underlying mechanisms are poorly understood. Here we show that cytotoxic CD8+ T lymphocytes, adaptive immune cells functionally underexplored in the aging central nervous system, drive axon degeneration, contributing to impairment of motor and cognitive performance in mice. We characterize CD8+ T cell populations in the adult and aged mouse brain by single-cell transcriptomics and identify heterogeneity and aging-related changes. Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated in aged, but not adult mice in the context of infection/systemic inflammation, well known risk factors for accelerated cognitive decline in the elderly. Thus, our study confirms that CD8+ T lymphocytes are important contributors to inflammation-driven damage of the aging CNS. Since we find similar T cell reactions in white matter autopsy material from normally aged humans, targeting CD8+ CNS-associated T cells in the elderly might mitigate aging-related decline of brain structure and function. To characterize CD8+ CNS-associated T cells we comprehensively analyzed their transcriptomic profiles using single-cell RNA sequencing of CD45highCD8+ T lymphocytes freshly sorted from 12- and 24-month-old brains. A total of 5,017 and 5,504 cells were captured and a median gene number per cell of 1,325 and 1,279 could be retrieved for adult and aged cells, respectively.