The aging of the adaptive immune system, made up of B cells and T cells, is a complex process. Broadly, the pace at which new adaptive immune cells are created declines to a tiny fraction of youthful levels in most people by age 50, and this lack of replacements allows the adaptive immune system to become ever more populated by exhausted, senescent, and malfunctioning cells. This decline in the supply of new adaptive immune cells is in part a problem of hematopoietic cells in the bone marrow, responsible for creating B cells and thymocytes that migrate to the thymus to mature into T cells. The decline is also in part a problem of the thymus, which atrophies with age, and of the lymphoid organs such as lymph nodes where B cells mature, which suffer their own age-related declines in structure and function.
Beyond the problems that arise from impaired replenishment of the adaptive immune system populations, it is also the case that immune cells, like all other cells, exist in the aged tissue environment, and will react in some combination of adaptive and maladaptive ways to the presence of damage, altered signaling, increased inflammation, and so forth. Today's open access paper presents data on what looks to be a consequence of this second class of issues, an altered secretion of signals by a subpopulation of T cells throughout the aged body that contributes to loss of cognitive function via disruption of normal operations in the hippocampus.
Relatedly, researchers are concerned about the infiltration of adaptive immune cells into the brain with advancing age. The brain is immunologically distinct from the body; it has its own classes of immune cell, and the blood-brain barrier prevents the passage of immune cells between body and brain. There are a few limited routes by which adaptive immune cells such as T cells find their way into the brain in very small numbers, but their presence in larger numbers is thought to be problematic. This occurs as the blood-brain barrier becomes dysfunctional and leaky with age, for example. Thus today's paper exists in the context in which researchers tend to think of T cells as harmful to the brain via infiltration into the central nervous system in later life, but in fact the problem exists even without that infiltration. The signals are the issue, and they readily pass into the brain once generated by immune cells outside the brain.
Aged circulating CD8+ T cells and their secreted factors drive cognitive decline
Transcriptional analyses of young and aged peripheral immune cells highlight changes in CD8+ T cells as a prominent hallmark of immune aging, with the emergence of an age-associated population characterized by expression of the serine protease granzyme K (GZMK). In the brain, infiltrating CD8+ T cells in aged mice decrease adult neurogenesis in the subventricular zone of the lateral ventricles, promote axon degeneration in the optic nerve, and induce neuroinflammation in the white matter. By contrast, only modest CD8+ T cell infiltration is reported in the aged hippocampus in the absence of neurodegenerative disease pathology in mouse models, while analysis of postmortem human hippocampi finds no age-related changes in infiltration.
Notwithstanding, despite the vast majority of CD8+ T cells residing in the periphery, the role of aged non-infiltrating circulating CD8+ T cells or their secreted factors in hippocampal-dependent cognitive decline is yet to be fully defined. We therefore sought to investigate the effect of peripheral aged CD8+ T cells on the hippocampus and ascertain the rejuvenating potential of selectively targeting this immune cell population in circulation at old age.
Using heterochronic parabiosis, we demonstrated that aged circulating CD8+ T cells were refractory to a young systemic environment, maintaining properties intrinsic to their cellular age. Systemic exposure of young mice to aged circulating CD8+ T cells elicited hippocampal aging transcriptional signatures and cognitive decline, which were attenuated by blocking T cell activation. We further showed that targeting aged circulating CD8+ T cells restored synaptic-related hippocampal signatures and ameliorated age-related cognitive impairments. Mechanistically, we demonstrated that GZMK, secreted by age-associated CD8+ T cells, impaired cognitive function, and inhibition of systemic GZMK in aged mice restored cognition. These findings identify activated aged circulating CD8+ T cells and their secreted factors as drivers of hippocampal-dependent cognitive decline in aging.
View the full article at FightAging
