Unraveling the dual nature of brain CD8⁺ T cells in Alzheimer’s disease

Excerpt

CD8⁺ T cells are essential components of adaptive immunity, and primarily function as cytotoxic T lymphocytes (CTLs) that recognize and eliminate infected or abnormal cells in the body. However, a small subpopulation of CD8⁺ T cells act as regulatory T cells (CD8⁺ Tregs) that suppress immune responses [1]. For a considerable period, it was widely held that the central nervous system (CNS) was immune privileged and impervious to T cells. However, over the past decade, research conducted in both murine and human subjects has unequivocally demonstrated the existence of brain-resident memory T cells [2]. T-cell migration to specific locations in response to inflammation and infections is orchestrated by interactions between chemokines and their receptors [3]. Beta-amyloid (Aβ) plaque deposition in the brain is one of the hallmark pathologies of Alzheimer’s disease (AD). Microglia, the brain’s innate immune cells, clear Aβ plaques. As AD advances, microglia may gradually lose their ability to eliminate these plaques effectively, and, in turn, begin to generate inflammatory mediators that could potentially expedite the progression of Aβ plaque accumulation [4]. In a recent study, Su et al. established a link between chemokine-chemokine receptor interaction, brain-infiltrating CD8⁺ T cells, and microglia in AD pathogenesis (Fig. 1A). Researchers demonstrated in an Aβ-driven AD mouse model (5xFAD mice) that chemokine CXCL16, secreted by microglia, attracted peripheral blood CD8⁺ T cells expressing CXCR6, which is a receptor for CXCL16. This attraction led these CD8⁺ T cells to enter the brain and migrate to the proximity of amyloid beta (Aβ) plaques, where CXCL16-secreting microglia were also found [5]. Su et al. reported that, instead of functioning as CTLs, these CXCR6⁺CD8⁺ T cells underwent clonal expansion in the brain, becoming PD-1⁺ and operating as Tregs. They alleviated the inflammatory state of microglia, ultimately leading to a reduction in Aβ plaque burden and mitigation of cognitive decline [5]. One of the most groundbreaking aspects of Su et al.’s study lies in its observation of the protective role of CD8⁺ T cells in AD development. This is particularly noteworthy when considering another recent and highly regarded study conducted by Chen et al. in a tauopathy mouse model of AD (TE4 mice) [6]. Chen et al. also reported microglia-mediated infiltration of T cells in the brain during neurodegeneration and tauopathy-associated T cell clonal expansion. However, in this AD model, CD8⁺ T cells were identified as contributors to a detrimental role in the neurodegeneration [6] (Fig. 1B). …