AGED CD8+ T CELLS DRIVE COGNITIVE DECLINE VIA GZMK [transfer]

Changes in peripheral CD8+ T cells are a prominent hallmark of immune aging. While infiltrating CD8+ T cells are implicated in aging and neurodegenerative disease-related pathology in the brain, the role of aged non-infiltrating CD8+ T cells has yet to be fully defined. Here, we show that targeting activated aged peripheral CD8+ T cells rescues age-related cognitive decline. Using heterochronic parabiosis and single cell transcriptomics analysis we observed that aged peripheral CD8+ T cells maintain properties intrinsic to their age, being refractory to the effects of a young or aged systemic milieu. Systemic exposure of young mice to aged CD8+ T cells elicited synaptic-related aging transcriptional signatures in the hippocampus and impaired cognition. Inhibiting migration of aged peripheral CD8+ T cells to lymph nodes mitigated pro-aging effects on the young hippocampus. Conversely, targeting aged CD8+ T cells restored synaptic-related signatures in the aged hippocampus and ameliorated cognitive impairments. Mechanistically, we identified granzyme k (GZMK) as a secreted age-associated CD8+ T cell-derived factor that impairs cognitive function. Together, our data identify activated aged CD8+ T cells and their secreted factors as potential therapeutic targets to rescue cognition in old age. We sought to investigate functionally how aged CD8+ T exerted their pro-aging effects on the young hippocampus. Activation of memory CD8+ T cells is dependent on G?i/o-coupled G protein-coupled receptor (GPCR)-mediated migration to lymph nodes. Correspondingly, we pre-treated aged CD8+ T cells with pertussis toxin (PTx), a known inhibitor of Gi/o protein signaling, to block migration into lymph nodes following adoptive transfer. Specifically, we performed an adoptive transfer of PTx or vehicle treated aged (26 months) CD8+ T cells into young (5 months) mice, and vehicle treated young CD8+ T cells into age-matched young animals as a baseline control for age-related changes. PTx pre-treatment has been shown to prevent T cell migration to lymph nodes without altering migration to open circulation tissues such as spleen, bone marrow, or liver, Moreover, the timeframe used for our studies was selected in line with previous reports showing minimal entry into the brain parenchyma with no impact on migration to the brain by PTx treatment. To investigate the impact on the young hippocampus, we performed single nucleus RNA seq (snRNAseq) analysis. Having observed pro-aging effects of aged circulating CD8+ T cells in the young hippocampus, we conversely explored the possibility that targeting CD8+ T cells can rescue cognitive function in aged mice. To selectively target aged peripheral CD8+ T cells late in life, aged (22 months) mice were given intraperitoneal injections of a CD8a depleting antibody or IgG2b isotype control. To investigate molecular changes elicited in the aged hippocampus following depletion of aged peripheral CD8+ T cells, we performed snRNAseq.