Studies in mice reveal how aging immune cells impair memory outside the brain and show that blocking CD8+ T cell activity or their secreted factor, granzyme K, can help restore cognitive abilities in older animals.
Study: Aged circulating CD8+ T cells and their secreted factors cause cognitive decline. Image credit: Juan Gaertner / Shutterstock
Recent mouse research has been published in a magazine immunity suggest that aged circulating cluster of differentiation 8 (CD8+) T cells and their secreted factors may cause hippocampus-dependent cognitive decline.
Aging CD8+ T cells and cognition
Aging is associated with cognitive decline, and identifying the underlying peripheral molecular and cellular factors is essential to restore cognitive function. Research suggests a novel role for age-related peripheral immune changes in brain dysfunction. Transcriptional analysis reveals that changes in CD8+ T cells are a hallmark of immunosenescence. However, the role of senescent non-infiltrating CD8+ T cells in cognitive decline remains poorly defined.
Peripheral T cells and hippocampal findings
In this study, researchers investigated the effects of aging circulating CD8+ T cells on the hippocampus. First, 4-month-old (young) and 20-month-old (old) mice were paired in heterochronous (young-old) and isochronous (old and young-young) symbiotic pairs. Memory and effector CD8+ and CD4+ T cells were increased, whereas naive CD8+ and CD4+ T cells were decreased in aged isochronous parabionts compared to their young isochronous counterparts.
Additionally, age-related effector memory CD8+ T cells emerged in aged isochronous parabionts. CD8+ T cells maintained age-specific properties that were largely unresponsive to the age of the systemic environment. Next, to examine the senescence-promoting potential of senescent peripheral CD8+ T cells on young hippocampi, the research team performed adoptive transfer of young or senescent CD8+ T cells into young mice. Infiltration of CD8+ T cells into the young hippocampus was minimal.
Bulk RNA-seq analysis identified 2,080 genes that were differentially expressed in the hippocampus of animals exposed to senescent CD8+ T cells compared to controls. Gene ontology analysis of down- and up-regulated genes reveals biological processes related to synaptic plasticity. Furthermore, quantitative polymerase chain reaction (qPCR) revealed decreased hippocampal expression of genes involved in synaptic plasticity, such as Homer1, calcium/calmodulin-dependent protein kinase 2 (CamkII), and Synapsin1.
CD8+ activation and memory decline
Additionally, we assessed hippocampus-dependent learning and memory using the radial arm water maze (RAWM) and novel object recognition (NOR) tests. Young mice exposed to aged CD8+ T cells showed impairments in learning and memory. To understand how senescent CD8+ T cells exert their pro-senescent effects, we pretreated these cells with pertussis toxin (PTx). PTx inhibits Gαi/o-coupled G protein-coupled receptor-mediated signaling on which many CD8+ T cell functions depend.
Vehicle-treated young CD8+ T cells and vehicle- or PTx-treated senescent CD8+ T cells were subsequently transplanted into young mice. PTx treatment increased the frequency of CD8+ T cells in circulation but decreased their frequency in lymph nodes. Significant transcriptional changes were observed in the hippocampus of young animals exposed to vehicle-treated senescent CD8+ T cells, which were largely recovered in the PTx group.
Additionally, the researchers performed in vitro activation of aged and young CD8+ T cells before adoptive transfer into young mice. Exposure to activated senescent CD8+ T cells increased errors in the RAWM test compared to exposure to young activated CD8+ T cells, regardless of PTx treatment. However, no behavioral changes were observed in young mice exposed to young CD8+ T cells or PTx-treated young CD8+ T cells, suggesting that CD8+ T cell activation causes cognitive decline.
Furthermore, ex vivo inhibition of senescent CD8+ T cell activation by tofacitinib treatment before transplantation attenuated cognitive impairment in young mice. In contrast, blocking tissue invasion with strong T-cell barrier interactions and anti-VLA-4 anti-VLA-4 did not provide the same relief, further suggesting that activation and cytokine release rather than parenchymal infiltration alone contribute to the pro-senescence effect. Further experiments revealed that targeting aged peripheral CD8+ T cells restored hippocampal transcriptional profiles and cognitive function. Circulating systemic factors released by activated senescent CD8+ T cells may promote cognitive decline, given their pro-senescence effects.
GZMK and brain barrier mechanism
The research team focused on granzyme K (GZMK), an age-associated CD8+ T cell-derived circulating factor associated with age-related effector memory CD8+ cells, and confirmed that these cells exclusively showed higher GZMK expression in aged isochronous parabionts. Young mice exposed to young CD8+ T cells expressing GZMK showed cognitive impairment in the RAWM test. Higher levels of plasma GZMK were detected in aged mice and young animals exposed to senescent CD8+ T cells, but not with PTx treatment.
Increased circulating GZMK in young mice increased errors in the RAWM test compared to young controls. Of note, although the precise barrier cell populations and downstream mechanisms are not completely understood, the cognitive impairment caused by circulating GZMK derived from senescent CD8+ T cells is likely mediated in part by interaction with brain barrier cells. Furthermore, targeting circulating GZMK with an inhibitor in aged mice reduced errors during RAWM testing compared to vehicle-treated aged controls.
Immunosenescence and the impact of cognitive therapy
In summary, in a preclinical mouse model, hippocampus-dependent cognitive decline was caused by activated senescent peripheral CD8+ T cells and their secreted factor GZMK. Mechanistically, interactions between senescent CD8+ T cells, GZMK, and brain barrier cells appear to contribute to cognitive impairment, but the identity of the barrier cells involved remains unclear. The authors also note that brain and body aging likely involves multiple circulating factors, and that GZMK is not restricted to CD8+ T cells.
Overall, this finding identified circulating factors secreted by aged peripheral CD8+ T cells as potential therapeutic targets that could restore aspects of cognition in aged mice and improve cognitive outcomes in old age.
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