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Review
. 2023 Apr 4:14:1154699.
doi: 10.3389/fimmu.2023.1154699. eCollection 2023.

T cell aging and Alzheimer's disease

Lin Guo  1 , Xiaoting Li  1   2 , Timothy Gould  3 , Zhan-You Wang  1 , Wenqiang Cao  1
Affiliations
Review

T cell aging and Alzheimer's disease

Lin Guo et al. Front Immunol. .

Abstract

The brain has long been considered an immune-privileged organ due to the presence of the blood-brain barrier (BBB). However, recent discoveries have revealed the underestimated role of T cells in the brain through the meningeal lymphatic system. Age is the primary risk factor for Alzheimer's disease (AD), resulting in marked age-dependent changes in T cells. Manipulating peripheral T cell immune response has been shown to impact AD, but the relationship between T cell aging and AD remains poorly understood. Given the limited success of targeting amyloid beta (Aβ) and the growing evidence of T cells' involvement in non-lymphoid organ aging, a deeper understanding of the relationship between T cells and AD in the context of aging is crucial for advancing therapeutic progress. In this review, we comprehensively examine existing studies on T cells and AD and offer an integrated perspective on their interconnections in the context of aging. This understanding can inform the development of new interventions to prevent or treat AD.

Keywords: Alzheimer’s disease (AD); T cell aging; neuroinflammation; senescence; thymic involution.

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Conflict of interest statement

Author TG was employed by company Rubedo Life Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Age-related changes in the T cell. Self-renewal of naïve T cell cells via homeostatic proliferation often fails in old individuals: 1) memory differentiation driven by homeostatic cytokines; 2) death due to lack of survival signal. Age also leads to significant changes in naïve T cell compartment: more differentiated states, increased heterogeneity, and reduced quiescence. Those changes in naïve T cells combined with changes in activation stages result in dysfunctions in aged effector or memory T cells. Furthermore, age impairs the function of existing memory.
Figure 2
Figure 2
T cell aging and AD. With age, the number of naïve T cells decreases, and relative memory T cells (Th1 and Th17 for CD4 T cells, TEMRA, or virtual memory for CD8 T cells) accumulate. Cytokines secreted by aged T cells increase the permeability of BBB, which increases other immune cells or their entry into the brain. On the one hand, aged T cells in the brain directly contribute to neuroinflammation and damage to the nervous system by releasing cytokines. Aged T cells in the brain worsen the pathology of AD via the accumulation of senescent cells. TNFα, IL-17, and GZMK from aged T cells probably induce senescence in brain cells. Furthermore, increased PD-1 or decreased perforin in aged CD8 T cells in the brain inhibits the clearance of senescent cells. Aβ: amyloid β, TEMRA: T effector memory CD45RA+. SASP: senescence-associated secretory phenotype.
See this image and copyright information in PMC

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