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Cytotoxic T lymphocytes limit Alzheimer's pathology


In Alzheimer's disease, but also in other neurodegenerative diseases, innate immunocompetent cells in the brain, the so-called microglia, produce a number of inflammatory cytokines. In addition, cells of the learnt, adaptive immunity, such as CD8-positive T lymphocytes, also enter the brain. Whether these cells play a protective or a damaging role in neurological diseases is still controversial.


In a paper published last year in Nature Immunology, Wei Su and his colleagues led by Hongbo Chi from the Immunology department at St. Jude Children's Hospital in Memphis, Tennessee (USA), were able to show that Alzheimer's disease leads to an accumulation of CD8+ T cells. They apparently play a protective role, as they can limit microglial activity, Aβ formation and memory loss.

Using single-cell RNA and T-cell antigen receptor (TCR) sequencing, the authors identified a chemokine receptor (CXCR6) that is necessary for the accumulation of CD8+ T cells in the brain. They were able to show that the recruitment of lymphocytes in so-called 5×FAD mouse brains, an animal model of Alzheimer's disease, requires the microglial production of a CXCR6-associated chemokine (CXCL16). Interestingly, CXCL16 is elevated in the post-mortem brain tissue of late-stage Alzheimer's patients.

In contrast, CD8+ T cells were significantly reduced in CXCR6-deficient 5×FAD mice. In addition, increased Aβ accumulation and poorer cognitive function were also detectable compared to control animals. High-resolution imaging of 5×FAD brains showed colocalisation of CD8+ T cells with microglia in the vicinity of Aβ plaques, which is also observed in the brains of patients with Alzheimer's disease.

Taken together, the results suggest that a CXCL16-CXCR6 axis recruits cytotoxic CD8+ T cells into Alzheimer's brains to suppress microglial functions and reduce disease pathology. Indeed, Alzheimer's mice lacking all T and B cells and natural killer cells show increased symptomatology in various neurodegenerative diseases.

References:

Su W, Saravia J, Risch I, ..., Peng J, Chi H (2023) CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology. Nature Immunology 24:1735


Foley JF (2023) Restraining neuroinflammation in Alzheimer's disease. Science Signaling 16:eadl4458

Image credit: iStock/selvanegra

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