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Cytotoxic T Cells in the Aging Brain Contribute to Neurodegeneration


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Posted 03 May 2021 - 07:55 PM


The aging of the immune system causes a great deal of damage, and in many different ways. There are many varieties of immune cell in the innate and adaptive portions of the immune system, and pathological subsets are known to arise with age. Take age-associated B cells, for example, or the misconfigured T cells that contribute to varieties of autoimmune disorder, or the regulatory T cells that contribute to the pathology of heart failure, or the macrophages that become foam cells to accelerate atherosclerosis. There are many more examples.

To a first approximation, the immune system of the central nervous system is distinct from that of the rest of the body. The blood-brain barrier separates the two sides, allowing only some traffic to pass between. When looking closer, this is not entirely true, however. T-cells of the adaptive immune system can cross into the cerebrospinal fluid in small numbers, particularly in disease states, and there is evidently some mode of communication between the immune systems of the central nervous system and the rest of the body, given that they both respond to threats that occur on only one side of the blood-brain barrier.

Researchers here present evidence for aggressive, cell-killing T cells to make their way to the brain in increasing numbers with age, and there cause problems that contribute to neurodegeneration and cognitive decline. Whether this is an extension of the existing and better regulated traffic that takes place in youth, or the consequence of blood-brain barrier dysfunction, or some other collection of mechanisms to allow passage, remains an open question.

Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline

Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon-myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages - important representatives of the innate immune system - are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses.

Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify 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 by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function.


View the full article at FightAging




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