A mouse study reveals how aging immune cells may impair memory outside the brain, showing that blocking CD8+ T cell activity or their secreted factor, granzyme K, helped restore cognitive performance in aged animals.
Study: Aged circulating CD8+ T cells and their secreted factors drive cognitive decline. Image Credit: Juan Gaertner / Shutterstock
A recent mouse study published in the journal Immunity suggests that aged circulating cluster of differentiation 8 (CD8+) T cells and their secreted factors can drive hippocampal-dependent cognitive decline.
Aged CD8+ T Cells and Cognition
Aging is linked to cognitive decline, and identifying the underlying peripheral molecular and cellular drivers is essential to restoring cognition. Studies suggest an emerging role of age-related peripheral immune changes in brain dysfunction. Transcriptional analyses reveal that changes in CD8+ T cells are a hallmark of immune aging. However, the role of aged, non-infiltrating CD8+ T cells in cognitive decline remains poorly defined.
Peripheral T Cells and Hippocampal Findings
In the present study, researchers investigated the effects of aged circulating CD8+ T cells on the hippocampus. First, mice aged 4 months (young) and 20 months (old) were paired in heterochronic (young-old) and isochronic (old-old and young-young) parabiotic pairs. Memory and effector CD8+ and CD4+ T cells increased, while naïve CD8+ and CD4+ T cells decreased in aged isochronic parabionts relative to young isochronic counterparts.
Moreover, age-related effector memory CD8+ T cells appeared in aged isochronic parabionts. CD8+ T cells maintained their age-intrinsic properties, which were largely refractory to the age of the systemic milieu. Next, to explore the pro-aging potential of aged peripheral CD8+ T cells on the young hippocampus, the team performed adoptive transfer of young or aged CD8+ T cells into young mice. There was minimal infiltration of CD8+ T cells into the young hippocampus.
Bulk RNA sequencing analysis identified 2,080 differentially expressed genes in the hippocampus of animals exposed to aged CD8+ T cells relative to controls. Gene ontology analysis of downregulated and upregulated genes revealed biological processes related to synaptic plasticity. In addition, quantitative polymerase chain reaction (qPCR) revealed reduced hippocampal expression of genes involved in synaptic plasticity, including Homer1, calcium/calmodulin-dependent protein kinase 2 (CamkII), and Synapsin1.
CD8+ Activation and Memory Decline
Further, radial arm water maze (RAWM) and novel object recognition (NOR) tests were used to assess hippocampal-dependent learning and memory. Young mice exposed to aged CD8+ T cells showed impairments in learning and memory. To understand how aged CD8+ T cells exerted pro-aging effects, these cells were pre-treated with pertussis toxin (PTx), which inhibits Gαi/o-coupled G protein-coupled receptor-mediated signaling, on which many CD8+ T cell functions depend.
Subsequently, vehicle-treated young CD8+ T cells and vehicle- or PTx-treated aged CD8+ T cells were transferred into young mice. PTx treatment increased the frequency of CD8+ T cells in circulation but decreased their frequency in lymph nodes. Prominent transcriptional changes were observed in the hippocampus of young animals exposed to vehicle-treated aged CD8+ T cells, which were largely restored in the PTx group.
Further, the researchers performed in vitro activation of aged and young CD8+ T cells before adoptive transfer into young mice. Exposure to activated aged CD8+ T cells increased errors in the RAWM test relative to exposure to young activated CD8+ T cells, irrespective of PTx treatment. However, no behavioral changes were noted in young mice exposed to young CD8+ T cells or PTx-treated young CD8+ T cells, suggesting that CD8+ T cell activation drives cognitive decline.
Moreover, ex vivo inhibition of aged CD8+ T cell activation with tofacitinib treatment before transfer alleviated cognitive deficit in young mice. By contrast, blocking strong T cell-barrier interaction and tissue entry with anti-VLA-4 did not produce the same rescue, further suggesting that activation and cytokine release, rather than parenchymal infiltration alone, contributed to the pro-aging effects. Further experiments revealed that hippocampal transcriptional profiles and cognitive function were restored by targeting aged peripheral CD8+ T cells. Circulating systemic factors released by activated aged CD8+ T cells may promote cognitive decline, given their pro-aging effects.
GZMK and Brain Barrier Mechanisms
The team focused on granzyme K (GZMK), an age-associated CD8+ T cell-derived circulating factor linked to age-related effector memory CD8+ cells, and confirmed that these cells exclusively exhibited higher GZMK expression in aged isochronic parabionts. Young mice exposed to GZMK-expressing young CD8+ T cells showed cognitive deficits in the RAWM test. Higher levels of plasma GZMK were detected in aged mice and in young animals exposed to aged CD8+ T cells, but not with PTx treatment.
Increasing circulating GZMK in young mice resulted in more errors in the RAWM test relative to young controls. Notably, cognitive impairments driven by circulating GZMK derived from aged CD8+ T cells were likely partly mediated by interactions with brain barrier cells, although the precise barrier-cell populations and downstream mechanisms were not fully resolved. Moreover, targeting circulating GZMK with an inhibitor in aged mice reduced errors during the RAWM test compared with vehicle-treated aged controls.
Immune Aging and Cognitive Therapy Implications
In sum, hippocampal-dependent cognitive decline was driven by activated aged peripheral CD8+ T cells and their secreted factor, GZMK, in preclinical mouse models. Mechanistically, interactions between aged CD8+ T cells, GZMK, and brain barrier cells appear to contribute to cognitive impairment, although the identity of the involved barrier cells remains unknown. The authors also note that brain-body aging likely involves multiple circulating factors, and that GZMK is not exclusive to CD8+ T cells.
Overall, the findings identify circulating factors secreted by aged peripheral CD8+ T cells as candidate therapeutic targets to restore aspects of cognition in aged mice and potentially improve cognitive outcomes in old age.
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