Alzheimer’s disease and the immune system: the emerging role of TEMRA cells

Alzheimer’s disease (AD) is the most common form of dementia, affecting millions worldwide. It is characterized by progressive cognitive decline and changes in behavior and personality, attributed to neuropathological changes, such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. While microglia, the resident immune cells in the brain, are well established as contributors in AD disease progression, recently, T cells in the periphery and the brain have also been highlighted as being important in the progression of AD, with CD8+ T cells reducing amyloid-β pathology and neurodegeneration by interacting with microglia (Su et al., 2023), while increasing tau-mediated neurodegeneration (Chen et al., 2023), showing the possibility of T cells to effect AD neuropathological changes, at least in animal models with specific and isolated AD-related pathologies. The potential role of T cells in people with AD dates to at least the 1980s (Lutshumba et al., 2021), with recent advancements in mass cytometry and single-cell RNA sequencing pointing to the expansion of an aging-associated T cell subpopulation, called terminally differentiated effector memory T cells re-expressing CD45RA, known as TEMRA cells, as a potential contributor to AD (Gate et al., 2020). This article explores the role of TEMRA cells in AD, focusing on two key questions: (1) what causes the increased presence of TEMRA cells in AD? (2) Are TEMRA cells merely biomarkers of AD progression, or do they actively contribute to the disease pathology? As we age, T cells gradually lose their function, reducing the body’s ability to mount specific immune responses to infections, cancers, and vaccines, known as immunosenescence. These age-related changes in T cells manifest as terminal differentiation, exhaustion, and senescence, particularly pronounced in CD8+ T cells, which are primarily pro-inflammatory. Both CD4+ and CD8+ T cell populations show reduced cytokine production and increased cytotoxic molecules such as granzyme K, which induces senescence in neighboring cells. In healthy individuals over 60 years old, approximately 60% of CD8+ T cells exhibit β-galactosidase activity, which is a hallmark of cellular senescence. Cellular senescence, often linked to DNA damage, telomere shortening, and mitochondrial failure, results in cells that no longer proliferate and are resistant to apoptosis. Senescent cells also produce a senescence-associated secretory phenotype, which is pro-inflammatory and can act as a paracrine signal to induce senescence in other cells (Soto-Heredero et al., 2023). TEMRA cells in Alzheimer’s disease—emerging evidence: TEMRA cells can be identified by their expression of surface markers CD45RA and CCR7. The expression of CD45RA and CCR7 is dependent on whether a cell has encountered its specific antigen and is capable of migrating to secondary lymphoid organs or not. Naïve cells begin expressing both CD45RA and CCR7. As they encounter different antigens, they lose these markers and differentiate into different cell types, such as memory, effector memory, or TEMRAs. TEMRAs re-express CD45RA, undergo extensive differentiation, exhibit potent cytotoxic capabilities, and have low proliferative capacity. CD8+ TEMRA cells can also be CD57+, a marker of senescence, enabling them to kill cells independently of TCR activation and antigen presentation. A subpopulation of CD4+ TEMRA cells that express GPR56 also express granzyme B and perforin, which is associated with a cytotoxic phenotype. These cells may correspond to CD4+ cytotoxic T lymphocytes, which increase with age and display markers of senescence, including DNA damage, decreased telomerase activity, and reduced proliferation. Like CD8+ TEMRAs, CD4+ cytotoxic T lymphocytes express markers of natural killer cells and may develop a natural killer-like phenotype (Soto-Heredero et al., 2023). The age-associated changes in T cell populations, particularly the accumulation of TEMRA cells, provide a foundation for understanding the potential role of TEMRA cells in AD (Lutshumba et al., 2021). Multiple studies have reported elevated levels of both CD4+ and CD8+ TEMRA cells in AD patients compared to age-matched controls, a change that appears to be specific to AD and not observed in other forms of dementia (Larbi et al., 2009; Gate et al., 2020; Gericke et al., 2023; van Olst et al., 2024). Interestingly, these alterations in TEMRA cell populations have been observed not only in AD patients but also in cognitively normal individuals with amyloid pathology, suggesting that these changes may occur early in the disease process (Gericke et al., 2023; Grayson et al., 2023). Thus, the accumulation of amyloid is associated with the accumulation of TEMRA cells. However, it is unknown if this is a causative or correlative relationship. Our recent work demonstrated that CD4+ TEMRA cells, but not CD8+ TEMRA cells, were associated with a decline in cognitive function as measured by the Mini-Mental State Examination. These TEMRA cells also positively correlated with established AD biomarkers, including serum Aβ42/40 ratio, neurofilament light, and glial fibrillary acidic protein levels, suggesting a potential link to ongoing neurodegenerative processes (Winford et al., 2024). Complementing our findings, studies using clinically diagnosed AD patients found associations between TEMRA cells and cerebrospinal fluid biomarkers such as pTau181 and Aβ42 (van Olst et al., 2024), further strengthening the TEMRA-neurodegeneration connection. Beyond quantitative changes, qualitative differences in AD TEMRA cells have been observed, including reduced CD28 expression, indicating potential functional alterations (Larbi et al., 2009). The TEMRA-AD relationship appears nuanced, with some studies reporting increased functional T cells in early stages, shifting towards exhausted phenotypes as cognitive impairment progresses (Grayson et al., 2023). Given the established link between TEMRA cells and AD, recent research has explored the influence of genetic risk factors, particularly APOE4, on TEMRA cell accumulation in AD. Gericke et al. (2023) showed that CD8+ TEMRA cells are increased in APOE4 carriers vs. non-carriers, while other studies show no differences (van Olst et al., 2024). However, it is important to note that in the former study, APOE4 carriers had higher loads of amyloid, which could also suggest a link between amyloid pathology and the accumulation of TEMRA cells. Interestingly, high genetic risk for AD based on polygenic risk scores was not associated with significant TEMRA cell alterations in cognitively healthy adults, indicating that these changes may be more closely tied to active disease processes rather than genetic predisposition alone (Deecke et al., 2024). What causes the increased presence of TEMRA cells in Alzheimer’s disease? In investigating potential causes of the TEMRA cells in AD, several studies have tested the association of latent viral infections. Cytomegalovirus (CMV) infection, in particular, has been consistently associated with expanded TEMRA cell populations in young and older adults (Gericke et al., 2023; Deecke et al., 2024). Gericke et al. (2023) found that all participants had IgG antibodies against various Herpesviridae above diagnostic thresholds, suggesting no association with Herpesviridae and TEMRAs. In contrast, CMV infection seropositivity has been consistently linked to elevated CD8+ TEMRA cell counts in both young and older adults, and this was confirmed by (Gericke et al., 2023; Deecke et al., 2024). Gericke et al. (2023) found that after adjusting for anti-CMV IgG titers, CD8+ TEMRA cells remained significantly elevated in amyloid-positive individuals compared to amyloid-negative controls. This suggests that while viral infections, particularly CMV, contribute to TEMRA cell expansion, they do not fully explain the increased presence of these cells in AD. Grayson et al. (2023) found increases in CMV-specific IFNγ+TNFα+ and IFNγ+IL-2– CD8+ T cells in amyloid-positive cognitively normal participants compared to the amyloid-negative cognitively normal participants. Gate et al. (2020) identified Epstein-Barr virus-specific T cell clones in the cerebrospinal fluid of AD patients, although these were not the most prevalent expanded clones. Thus, while latent viral infections, particularly CMV, contribute significantly to TEMRA cell expansion, they do not fully explain the increased presence of these cells in AD. Given the strong influence of CMV and other infections on TEMRA expression, the effect of AD on these cells may be underappreciated due to the presence of CMV in both the control and AD groups. The increased presence of TEMRA cells in AD has led to several hypotheses about their role in disease pathology. Recent studies have proposed three main models to explain the relationship between TEMRA cells, immune function, and cognitive decline in AD. Grayson et al. (2023) proposed two hypotheses to explain the relationship between T cells, infection, inflammation, and AD. Their favored model, the viral reactivation and T cell exhaustion hypothesis, suggests that individuals with strong T cell function can control chronic pathogens that nearly all humans carry. For reasons that are not defined, some people have diminished T cell function, which leads to pathogen reactivation, causing systemic inflammation, which drives amyloid production and cognitive impairment (Figure 1A). Their alternative dysfunctional T cell activation hypothesis proposes that T cells directly lead to cognitive impairment over time through cytokine production. This may be driven by microglia interaction with tau that leads to the recruitment of T cells to the brain (Chen et al., 2023; Grayson et al., 2023; Figure 1B).Figure 1: Hypotheses on the role of T cells in Alzheimer’s disease.This figure illustrates three hypotheses explaining the relationship between T cells, infection, inflammation, and Alzheimer’s disease. (A) The viral reactivation and T cell exhaustion hypothesis proposes that strong T cell function controls chronic pathogens (e.g., CMV and EBV), while weakened function (increased TEMRA cells, decreased T diversity) leads to pathogen reactivation. These triggers increased IFNγ production and innate immune responses, potentially causing neuroinflammation, neurodegeneration, and Aβ accumulation. (B) The dysfunctional T cell activation hypothesis suggests T cell dysfunction increases chemokine production and T cell brain recruitment, resulting in neuroinflammation and neurodegeneration, possibly driven by tau pathology. (C) The susceptibility to infection hypothesis posits that neuroinflammation triggers the release of immune modulators (e.g., glucocorticoids, acetylcholine, and cytokines), weakening T cell function (e.g., increased TEMRA cells, decreased cytokines, and reduced barrier protection). This weakened state increases susceptibility to severe infections, leading to recurring systemic inflammation, delirium, and further neuroinflammation. These infections, in turn, further impair T cell function, creating a self-perpetuating cycle of T cell exhaustion and increased vulnerability to infections. Created with BioRender.com. ↑ Indicates increase or upregulation; ↓ indicates decrease or downregulation. Aβ: Amyloid-beta; CMV: cytomegalovirus; EBV: Epstein-Barr virus; IFNγ: interferon gamma; TEMRA: T effector memory cells re-expressing CD45RA.Bachstetter et al. (2023) suggest a third perspective, the susceptibility to infection hypothesis. This hypothesis posits that neuroinflammation triggers the release of immune modulators (e.g., glucocorticoids, acetylcholine, and cytokines), weakening T cell function (characterized by increased TEMRA cells, decreased cytokine production, and reduced barrier protection). This weakened state increases susceptibility to severe infections, leading to recurring systemic inflammation, delirium, and further neuroinflammation. These infections, in turn, further impair T cell function, creating a self-perpetuating cycle of T cell exhaustion and increased vulnerability to infections. This cycle may have lasting effects on the brain and potentially accelerate cognitive decline, particularly in older adults with dementia (Bachstetter et al., 2023; Figure 1C). These hypotheses underscore the complex role of TEMRA cells in AD, but current cross-sectional studies cannot definitively determine their exact function. Longitudinal studies in diverse populations are crucial to clarify the temporal relationships between T cell function, exhaustion, infection susceptibility, and cognitive decline in AD. Such research could provide valuable insights into the role of TEMRA cells in AD pathogenesis across different populations, potentially leading to more targeted strategies for early diagnosis, prevention, and treatment of AD. Conclusion: The complex relationship between TEMRA cells, the aging immune system, and neurodegeneration in AD highlights key research priorities: (1) Longitudinally conduct longitudinal studies on TEMRA cells in AD progression; (2) investigate how TEMRA cells interact with AD pathology; (3) study diverse populations to understand genetic and environmental influences on TEMRA cells in AD; (4) quantify the number and significance of T cells in the brain, cerebrospinal fluid, and meninges in AD; (5) evaluate the interactions between TEMRA cells and microglia in AD. Unraveling the role of TEMRA cells in AD will require interdisciplinary collaboration to bridge knowledge gaps, enhance understanding of immune-AD interactions, and develop novel strategies to mitigate the disease’s societal impact. C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y