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Unraveling the dual nature of brain CD8+ T cells in Alzheimer’s disease
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2024-02-14 , DOI: 10.1186/s13024-024-00706-y
Dan Hu , Howard L. Weiner

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).

These two opposing findings raise the intriguing question: What factors contributed to the disparate conclusions regarding the role of CD8⁺ T cells in AD pathogenesis in these two studies? Here we discuss the differences between these two studies that might have contributed to the disparity. First, different AD mouse models were used. In the study conducted by Su et al., researchers utilized 5xFAD mice expressing human APP and PSEN1 transgenes, harboring a total of five AD-linked mutations. These mice are genetically engineered for the study of the Aβ pathology. On the other hand, in the study conducted by Chen et al., researchers focused on genetically further modified P301S Tau transgenic mice that co-expressed the E4 variant of the human APOE (APOE4) gene, abbreviated as the TE4 mice [6]. P301S Tau transgenic mice carry a transgene with the P301S mutation in the tau-encoding MAPT gene and develop tau pathology, and co-expression of the APOE4 gene aggravates AD-associated pathology. These two distinct models express different transgenic genes, develop different AD pathologies, and also exhibit temporal disparity in disease development [7] (see review by Yokoyama et al. [7] for more details on AD animal models and their applications). Hence, even though T cells were attracted to the brain and clonally expanded in both mouse models, the brain microenvironment for T cell proliferation and differentiation likely differed in these two studies. Secondly, the approaches employed to investigate the function of CD8⁺ T cells in the brain were different. Su et al. implemented genetic modifications in 5xFAD mice to specifically target T-cell migration and function. This included the creation of Cxcr6-deficient mice (blocking CXCL16-CXCR6 axis-mediated CXCR6⁺CD8⁺ T cell homing to the brain), B2m-deficient mice (blocking CD8⁺ T cell function), and Tcra-deficient mice (depleting T cells) [5] (Fig. 1A, right panel). These three approaches tackled the same question from different yet complementary angles, pinpointing CXCR6⁺ CD8⁺ T cells as the population that ameliorated AD pathologies. On the other hand, Chen et al. depleted both CD4⁺ and CD8⁺ T cells together by intraperitoneal injection of anti-CD4 and anti-CD8α antibodies (Fig. 1B, right panel), preventing brain T cell infiltration that protected mice from brain atrophy [6]. Chen et al. also reported that treatment with anti-PD-1 antibodies, previously known to ameliorate AD pathologies in both Aβ-driven and tauopathy AD mouse models [8, 9], heightened the presence of FoxP3⁺ CD4⁺ Tregs without changing the frequency of Tauopathy-associated CD8⁺ T cells [6]. Given the strong correlation between T cell brain infiltration and tauopathy, along with the presence of disease-associated microglia (DAM), Chen et al. concluded that CD8⁺ T cells infiltrating the brain were detrimental, whereas FoxP3⁺ CD4⁺ Tregs were protective in this tauopathy AD model. In this study, researchers demonstrated that the overall depletion of T cells provided protection. However, the neurodegenerative effects of tauopathy-associated CD8⁺ T cells were primarily inferred through single-cell RNA-sequencing (scRNA-seq) analysis [6]. Collectively, the utilized animal models and methodologies varied in these two studies.

Upon careful examination of these two studies, we argue that the disparate conclusions regarding CD8⁺ T cell function in neurodegeneration were likely attributable to the use of different AD mouse models. Maintaining a delicate balance among the diverse components of the immune system is essential for optimal functioning. Variations in the intricate interplay of immune elements can significantly impact the ultimate outcome of immune responses. It is well known that tumor microenvironment heavily affects CD8⁺ T cell function and differentiation [10]. Conceivably, the disparities between the AD models utilized in these two studies could collectively give rise to distinct microenvironments at diseased sites for immune cells. Research is needed to explore the effects of the brain microenvironment on CD8⁺ T cell differentiation and plasticity. Hence, the variations in the microenvironment for CD8⁺ T cells between these distinct AD mouse models [5, 6] might have led to the preferential development and expansion of specific CD8⁺ T cell subtypes, such as CD8⁺ Tregs or CTLs. It is possible that several functionally distinct subtypes of CD8⁺ T cells co-exist in a diseased brain and the collective influence on AD pathologies is driven by a dominant subtype. Su et al. illustrated in their elegant study that the clonally expanded CD8⁺ T cells around Aβ plaques functioned as regulatory cells, restraining the activation status of DAMs. However, in the tauopathy mouse model, further experimental investigation is required to validate the neurodegenerative effects attributed to tauopathy-associated CD8⁺ T cells, such as exploring tauopathy in B2m-deficient TE4 mice.

Regarding cell markers, Su et al. showed that the brain regulatory CD8⁺ T cells that restrained Aβ plaque deposition and cognitive decline in 5xFAD mice were CXCR6⁺PD-1⁺ [5]. PD-1 is a marker for T-cell exhaustion [11]. The finding that immune checkpoint blockade targeting PD-1 reduces AD pathologies in 5xFAD mice [9] can be used as supporting evidence to the theory that checkpoint blockade rejuvenates the protective function of exhausted PD-1⁺ regulatory CD8⁺ T cells. Interestingly, Chen et al. also observed CXCR6 and PD-1 expression in brain T cells that promoted tauopathy in TE4 mice, and reported that anti-PD-1 treatment increased the activity of PD-1⁺ CD4⁺ Tregs but did not alter the activity of detrimental PD-1⁺ CD8⁺ T cells [6]. Chen et al. implied that increased CD4⁺ Treg activity was the underlying mechanism for the previous observation that immune checkpoint blockade targeting PD-1 ameliorates tauopathy [6, 8]. It is known that both mouse and human brain CD8⁺ T cells exhibit tissue-resident memory T cell signatures, express PD-1, and are enriched for tissue-homing associated chemokine receptors, including CXCR6 [2, 12]. Hence, the phenotype of CXCR6⁺PD-1⁺ of brain T cells in both studies [5, 6] might only reflect that these were brain-resident cells instead of an association of cellular function, while the elevated PD-1 expression might merely signify the exhaustion state of these cells. It is crucial to identify the specific CD8⁺ T cell subtype(s) present in the brain and understand their rejuvenation potential when contemplating repurposing anti-PD-1 antibodies, originally designed for anticancer purposes, for the treatment of AD. Consequently, there is a need for novel markers to differentiate functionally distinct subtypes of CD8⁺ T cells in AD pathogenesis.

Clonal expansion of CD8⁺ T cells in the CNS has been linked to Alzheimer’s disease, Parkinson’s disease (PD), and multiple sclerosis (MS) in humans (reviewed by Hu et al. in [13]). We have previously argued that the similarities in cell surface markers and gene signatures between human clonally expanded CD8⁺ T cells in CSF and CD8⁺ Tregs suggest the potential existence of both protective and detrimental subsets within the neurodegeneration-associated CD8⁺ cell population [13, 14]. The two studies by Su et al. and Chen et al. in AD mouse models provide direct in vivo evidence supporting this notion. Moreover, prior to the observation of CXCL16-CXCR6 mediated CD8 T cell infiltration in the mouse models, the CXCL16-CXCR6 axis-mediated CXCR6⁺ CD8 T cell homing to cerebrospinal fluid (CSF) followed by clonal expansion of the cells has been suggested in patients with cognitive impairment [15]. These correlations between humans and mice indicate that these two studies have established valuable platforms for exploring critical questions such as which cell markers or gene signatures distinguish the protective and detrimental brain CD8⁺ T cell subtypes, how the brain microenvironment impacts the development and function of these cells, and how brain CD8⁺ T cells regulate microglia function. Considering the prevalence of clonally expanded CD8⁺ T cells in AD, PD, and MS, exploring these questions not only has the potential to reveal new insights into AD pathogenesis but also holds broader implications for the overarching field of neuroimmunology, encompassing the pathogenesis of PD and MS as well.

Not applicable.

Aβ:: amyloid beta
AD:: Alzheimer’s disease
APOE4 :: E4 variant of the APOE gene
A/PE4 mouse:: human APOE4-expressing APP/PS1-21 mouse
CD8⁺ Treg:: CD8⁺ regulatory T lymphocyte
CNS:: central nervous system
CTL:: cytotoxic T cell
DAM:: disease-associated microglia
HSC:: hematopoietic stem cell
MS:: multiple sclerosis
PD:: Parkinson’s disease
TE4 mouse:: human APOE4-expressing P301S Tau transgenic mouse
5xE4 mouse:: human APOE4-expressing 5xFAD mouse

Nakagawa H, Wang L, Cantor H, Kim HJ. New insights into the Biology of CD8 Regulatory T cells. Adv Immunol. 2018;140:1–20.
Article CAS PubMed Google Scholar
Smolders J, et al. Tissue-resident memory T cells populate the human brain. Nat Commun. 2018;9:4593.
Article PubMed PubMed Central Google Scholar
Krummel MF, Bartumeus F, Gerard A. T cell migration, search strategies and mechanisms. Nat Rev Immunol. 2016;16:193–201.
Article CAS PubMed PubMed Central Google Scholar
Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–72.
Article CAS PubMed PubMed Central Google Scholar
Su W, et al. CXCR6 orchestrates brain CD8(+) T cell residency and limits mouse Alzheimer’s disease pathology. Nat Immunol. 2023;24:1735–47.
Article CAS PubMed Google Scholar
Chen X, et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023;615:668–77.
Article CAS PubMed Google Scholar
Yokoyama M, Kobayashi H, Tatsumi L, Tomita T. Mouse models of Alzheimer’s Disease. Front Mol Neurosci. 2022;15:912995.
Article CAS PubMed PubMed Central Google Scholar
Rosenzweig N, et al. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019;10:465.
Article CAS PubMed PubMed Central Google Scholar
Baruch K, et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat Med. 2016;22:135–7.
Article CAS PubMed Google Scholar
Maimela NR, Liu S, Zhang Y. Fates of CD8 + T cells in Tumor Microenvironment. Comput Struct Biotechnol J. 2019;17:1–13.
Article CAS PubMed Google Scholar
Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015;6:7–17.
PubMed PubMed Central Google Scholar
Altendorfer B, et al. Transcriptomic profiling identifies CD8(+) T cells in the brain of aged and Alzheimer’s Disease Transgenic mice as tissue-Resident memory T cells. J Immunol. 2022;209:1272–85.
Article CAS PubMed PubMed Central Google Scholar
Hu D, Xia W, Weiner HL. CD8(+) T cells in neurodegeneration: friend or foe? Mol Neurodegener. 2022;17:59.
Article PubMed PubMed Central Google Scholar
Hu D, Murugaiyan G. CD8(+) tregs kill pathogenic cells to avert autoimmunity. Trends Immunol. 2022;43:415–6.
Article CAS PubMed Google Scholar
Piehl N, et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell. 2022;185:5028–5039e5013.
Article CAS PubMed PubMed Central Google Scholar

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D. H. is supported, in part, by National Multiple Sclerosis Society Research Grant RG-2111-38681 (to D.H.) and Brigham and Women’s Hospital Faculty Career Development Award (to D. H.).

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Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 02115, Boston, MA, USA
Dan Hu & Howard L. Weiner

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DH and HLW wrote the manuscript. The authors read and approve the final manuscript.

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Hu, D., Weiner, H.L. Unraveling the dual nature of brain CD8⁺ T cells in Alzheimer’s disease. Mol Neurodegeneration 19, 16 (2024). https://doi.org/10.1186/s13024-024-00706-y

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Received: 27 November 2023
Accepted: 22 January 2024
Published: 14 February 2024
DOI: https://doi.org/10.1186/s13024-024-00706-y

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Keywords

Alzheimer’s disease
CD8⁺ T cells
Microglia

中文翻译：

揭示阿尔茨海默病中大脑 CD8+ T 细胞的双重性质

CD8 ⁺ T 细胞是适应性免疫的重要组成部分，主要发挥细胞毒性 T 淋巴细胞 (CTL) 的作用，识别并消除体内受感染或异常的细胞。然而，一小部分 CD8 ⁺ T 细胞充当调节性 T 细胞 (CD8 ⁺ Tregs)，抑制免疫反应 [1]。在相当长的一段时间内，人们普遍认为中枢神经系统 (CNS) 具有免疫特权，不受 T 细胞的影响。然而，在过去的十年中，对小鼠和人类受试者进行的研究明确证明了大脑驻留记忆 T 细胞的存在 [2]。 T 细胞响应炎症和感染而迁移到特定位置是通过趋化因子及其受体之间的相互作用来协调的 [3]。大脑中的β-淀粉样蛋白（Aβ）斑块沉积是阿尔茨海默病（AD）的标志性病理学之一。小胶质细胞是大脑的先天免疫细胞，可以清除 Aβ 斑块。随着 AD 的进展，小胶质细胞可能逐渐失去有效消除这些斑块的能力，反过来，开始产生炎症介质，可能会加速 Aβ 斑块积累的进展 [4]。在最近的一项研究中，Su 等人。建立了 AD 发病机制中趋化因子-趋化因子受体相互作用、脑浸润 CD8 ⁺ T 细胞和小胶质细胞之间的联系（图 1A）。研究人员在 Aβ 驱动的 AD 小鼠模型（5xFAD 小鼠）中证明，小胶质细胞分泌的趋化因子 CXCL16 会吸引表达 CXCR6 的外周血 CD8 ⁺ T 细胞，CXCR6 是 CXCL16 的受体。这种吸引力导致这些 CD8 ⁺ T 细胞进入大脑并迁移到淀粉样蛋白 β (Aβ) 斑块附近，在那里还发现了分泌 CXCL16 的小胶质细胞 [5]。苏等人。报道称，这些 CXCR6 ⁺ CD8 ⁺ T 细胞并没有发挥 CTL 的作用，而是在大脑中进行克隆扩增，成为 PD-1 ⁺并作为 Tregs 发挥作用。它们减轻了小胶质细胞的炎症状态，最终导致 Aβ 斑块负担减少并缓解认知能力下降 [5]。 Su等人的研究最具开创性的方面之一在于其对CD8 ⁺ T细胞在AD发展中的保护作用的观察。当考虑到 Chen 等人最近进行的另一项备受关注的研究时，这一点尤其值得注意。 AD 的 tau 蛋白病小鼠模型（TE4 小鼠）[6]。陈等人。还报道了神经变性和 tau 蛋白病相关 T 细胞克隆扩张期间大脑中小胶质细胞介导的 T 细胞浸润。然而，在该 AD 模型中，CD8 ⁺ T 细胞被确定为在神经变性中发挥有害作用的因素 [6]（图 1B）。

这两项相反的发现提出了一个有趣的问题：哪些因素导致了这两项研究中关于 CD8 ⁺ T 细胞在 AD 发病机制中的作用的不同结论？在这里，我们讨论这两项研究之间可能导致这种差异的差异。首先，使用不同的 AD 小鼠模型。在 Su 等人进行的研究中，研究人员利用表达人类 APP 和PSEN1转基因的 5xFAD 小鼠，总共含有 5 个 AD 相关突变。这些小鼠经过基因工程改造，用于 Aβ 病理学研究。另一方面，在Chen等人进行的研究中，研究人员重点研究了基因进一步修饰的P301S Tau转基因小鼠，其共表达人类APOE（APOE4）基因的E4变体，简称TE4小鼠[6]。 P301S Tau 转基因小鼠在 tau 编码MAPT基因中携带带有 P301S 突变的转基因，并出现 tau 病理学，而APOE4基因的共表达会加剧 AD 相关病理学。这两种不同的模型表达不同的转基因基因，产生不同的 AD 病理学，并且在疾病发展方面也表现出时间差异 [7]（有关 AD 动物模型及其应用的更多详细信息，请参阅 Yokoyama 等人的评论 [7]）。因此，尽管 T 细胞在两种小鼠模型中都被吸引到大脑并进行克隆扩增，但这两项研究中 T 细胞增殖和分化的大脑微环境可能有所不同。其次，研究大脑中CD8 ⁺ T 细胞功能的方法不同。苏等人。对 5xFAD 小鼠进行基因改造，专门针对 T 细胞迁移和功能。这包括创建Cxcr6缺陷型小鼠（阻断 CXCL16-CXCR6 轴介导的 CXCR6 ⁺ CD8 ⁺ T 细胞归巢至大脑）、B2m缺陷型小鼠（阻断 CD8 ⁺ T 细胞功能）和Tcra缺陷型小鼠（耗尽 T细胞）[5]（图 1A，右图）。这三种方法从不同但互补的角度解决了同一问题，将 CXCR6 ⁺ CD8 ⁺ T 细胞确定为改善 AD 病理的群体。另一方面，陈等人。 CD4 ⁺和 CD8 ⁺均耗尽通过腹腔注射抗 CD4 和抗 CD8α 抗体将 T 细胞聚集在一起（图 1B，右图），防止脑部 T 细胞浸润，从而保护小鼠免遭脑萎缩 [6]。陈等人。还报道称，抗 PD-1 抗体治疗（之前已知可改善 Aβ 驱动型和 tau 病 AD 小鼠模型中的 AD 病理学 [8, 9]）可增强 FoxP3 ⁺ CD4 ⁺ Tregs 的存在，而不会改变 Tau 病的频率。相关的 CD8 ⁺ T 细胞 [6]。鉴于 T 细胞脑浸润与 tau 蛋白病之间的密切相关性，以及疾病相关小胶质细胞 (DAM) 的存在，Chen 等人。结论是，浸润大脑的CD8 ^{+ T 细胞是有害的，而 FoxP3}⁺ CD4 ⁺ Tregs 在此 tau 蛋白病 AD 模型中具有保护作用。在这项研究中，研究人员证明 T 细胞的整体耗尽可以提供保护。然而，tau 蛋白病相关 CD8 ⁺ T 细胞的神经退行性作用主要是通过单细胞 RNA 测序 (scRNA-seq) 分析推断的 [6]。总的来说，这两项研究中使用的动物模型和方法各不相同。

经过仔细检查这两项研究，我们认为关于 CD8 ⁺ T 细胞在神经退行性变中的功能的不同结论可能归因于使用不同的 AD 小鼠模型。维持免疫系统不同组成部分之间的微妙平衡对于实现最佳功能至关重要。免疫元素错综复杂的相互作用的变化可以显着影响免疫反应的最终结果。众所周知，肿瘤微环境严重影响CD8 ⁺ T细胞的功能和分化[10]。可以想象，这两项研究中使用的 AD 模型之间的差异可能共同导致患病部位的免疫细胞产生不同的微环境。需要研究探索大脑微环境对 CD8 ⁺ T 细胞分化和可塑性的影响。因此，这些不同 AD 小鼠模型之间 CD8 ⁺ T 细胞微环境的变化[5, 6] 可能导致特定 CD8 ⁺ T 细胞亚型（例如 CD8 ⁺ Tregs 或 CTL）的优先发育和扩增。患病大脑中可能存在几种功能不同的 CD8 ⁺ T 细胞亚型，并且对 AD 病理的集体影响是由一种主要亚型驱动的。苏等人。他们在精美的研究中表明，Aβ 斑块周围克隆扩增的 CD8 ⁺ T 细胞起到调节细胞的作用，抑制 DAM 的激活状态。然而，在 tau 蛋白病小鼠模型中，需要进一步的实验研究来验证 tau 蛋白病相关 CD8 ⁺ T 细胞引起的神经退行性影响，例如在B2m缺陷的 TE4 小鼠中探索 tau 蛋白病。

关于细胞标记，Su 等人。研究表明，抑制5xFAD小鼠Aβ斑块沉积和认知能力下降的大脑调节性CD8 ^{+ T细胞是CXCR6}⁺ PD-1 ⁺ [5]。 PD-1 是 T 细胞耗竭的标志物 [11]。针对 PD-1 的免疫检查点封锁可减少 5xFAD 小鼠的 AD 病理[9]，这一发现可以作为检查点封锁恢复耗尽的 PD-1 ⁺调节性 CD8 ⁺ T 细胞的保护功能这一理论的支持证据。有趣的是，陈等人。还观察到脑 T 细胞中 CXCR6 和 PD-1 的表达促进了 TE4 小鼠的 tau 蛋白病，并报道抗 PD-1 治疗增加了 PD-1 ⁺ CD4 ⁺ Tregs 的活性，但没有改变有害 PD-1 的活性⁺ CD8 ⁺ T 细胞 [6]。陈等人。表明 CD4 ⁺ Treg 活性增加是之前观察到的针对 PD-1 的免疫检查点阻断可改善 tau 蛋白病变的潜在机制 [6, 8]。众所周知，小鼠和人脑 CD8 ⁺ T 细胞都表现出组织驻留记忆 T 细胞特征，表达 PD-1，并且富含组织归巢相关趋化因子受体，包括 CXCR6 [2, 12]。因此，两项研究中脑 T 细胞的 CXCR6 ⁺ PD-1 ⁺表型[5, 6] 可能仅反映这些细胞是脑常驻细胞，而不是细胞功能的关联，而 PD-1 表达升高可能仅仅反映了这些细胞是脑内常驻细胞。表示这些细胞的耗尽状态。在考虑将最初设计用于抗癌目的的抗 PD-1 抗体重新用于治疗 AD 时，识别大脑中存在的特定CD8 ⁺ T 细胞亚型并了解其恢复活力的潜力至关重要。因此，需要新的标记物来区分 AD 发病机制中功能不同的 CD8 ⁺ T 细胞亚型。

CNS 中CD8 ⁺ T 细胞的克隆扩增与人类阿尔茨海默病、帕金森病 (PD) 和多发性硬化症 (MS) 有关（Hu 等人在 [13] 中进行了综述）。我们之前认为，脑脊液中人类克隆扩增的 CD8 ⁺ T 细胞和 CD8 ⁺ Tregs 之间的细胞表面标记和基因特征的相似性表明，神经退行性变相关的 CD8 ⁺细胞群中可能存在保护性和有害亚群 [13， 14]。 Su等人的两项研究。和陈等人。 AD小鼠模型中的研究提供了支持这一观点的直接体内证据。此外，在小鼠模型中观察到 CXCL16-CXCR6 介导的 CD8 T 细胞浸润之前，CXCL16-CXCR6 轴介导的 CXCR6 ⁺ CD8 T 细胞归巢至脑脊液 (CSF)，随后进行细胞克隆扩增。认知障碍患者[15]。人类和小鼠之间的这些相关性表明，这两项研究为探索关键问题建立了有价值的平台，例如哪些细胞标记或基因特征区分保护性和有害的大脑 CD8 ⁺ T 细胞亚型，大脑微环境如何影响这些细胞的发育和功能细胞，以及大脑 CD8 ⁺ T 细胞如何调节小胶质细胞功能。考虑到克隆扩增 CD8 ⁺ T 细胞在 AD、PD 和 MS 中的普遍存在，探索这些问题不仅有可能揭示 AD 发病机制的新见解，而且对神经免疫学的总体领域（包括 PD 的发病机制）具有更广泛的影响和 MS 也是如此。

不适用。

β：: β淀粉样蛋白
广告：: 阿尔茨海默氏病
载脂蛋白4：: APOE基因的 E4 变体
A/PE4鼠标：: 表达人APOE4的 APP/PS1-21 小鼠
CD8 ⁺调节性T细胞：: CD8 ⁺调节性T淋巴细胞
中枢神经系统：: 中枢神经系统
控制TL：: 细胞毒性T细胞
坝：: 疾病相关小胶质细胞
HSC：: 造血干细胞
多发性硬化症：: 多发性硬化症
PD：: 帕金森病
TE4鼠标：: 表达人APOE4的P301S Tau转基因小鼠
5xE4 鼠标：: 表达人APOE4的 5xFAD 小鼠

中川 H，王 L，坎托 H，金 HJ。对 CD8 调节性 T 细胞生物学的新见解。高级免疫学。 2018；140：1–20。
文章 CAS PubMed 谷歌学术
斯莫尔德斯 J 等人。组织驻留记忆 T 细胞分布在人脑中。纳特·康姆. 2018；9：4593。
文章 PubMed PubMed Central Google Scholar
Krummel MF、Bartumeus F、Gerard A. T 细胞迁移、搜索策略和机制。自然免疫学修订版。 2016；16：193–201。
文章 CAS PubMed PubMed Central Google Scholar
Hansen DV、Hanson JE、Sheng M。阿尔茨海默病中的小胶质细胞。 J 细胞生物学。 2018；217：459–72。
文章 CAS PubMed PubMed Central Google Scholar
苏伟，等。 CXCR6 协调大脑 CD8(+) T 细胞驻留并限制小鼠阿尔茨海默病病理学。自然免疫学。 2023；24：1735–47。
文章 CAS PubMed 谷歌学术
陈X，等。小胶质细胞介导的 T 细胞浸润会导致 tau 蛋白病的神经变性。自然。 2023；615：668–77。
文章 CAS PubMed 谷歌学术
Yokoyama M，Kobayashi H，Tatsumi L，Tomita T。阿尔茨海默病的小鼠模型。前摩尔神经科学。 2022；15：912995。
文章 CAS PubMed PubMed Central Google Scholar
罗森茨威格 N 等人。 PD-1/PD-L1 检查点阻断利用单核细胞衍生的巨噬细胞来对抗 tau 蛋白病小鼠模型中的认知障碍。纳特·康姆. 2019；10：465。
文章 CAS PubMed PubMed Central Google Scholar
巴鲁克 K 等人。 PD-1 免疫检查点阻断可减少阿尔茨海默病小鼠模型的病理并改善记忆。纳特医学。 2016；22：135–7。
文章 CAS PubMed 谷歌学术
Maimela NR，Liu S，Zhang Y。肿瘤微环境中 CD8 + T 细胞的命运。计算结构生物技术杂志，2019；17：1–13。
文章 CAS PubMed 谷歌学术
Lee J、Ahn E、Kissick HT、Ahmed R。通过阻断 PD-1 途径重振耗尽的 T 细胞。用于免疫病理治疗。 2015；6：7–17。
PubMed PubMed 中心 Google 学术搜索
阿尔滕多弗 B 等人。转录组分析将老年和阿尔茨海默病转基因小鼠大脑中的 CD8(+) T 细胞识别为组织驻留记忆 T 细胞。 J免疫学杂志。 2022；209：1272–85。
文章 CAS PubMed PubMed Central Google Scholar
胡 D，夏 W，韦纳 HL。 CD8(+) T细胞在神经退行性变中：朋友还是敌人？摩尔神经退行性疾病。 2022 年；17:59。
文章 PubMed PubMed Central Google Scholar
Hu D, Murugaiyan G. CD8(+) tregs 杀死致病细胞以避免自身免疫。趋势免疫学。 2022；43：415–6。
文章 CAS PubMed 谷歌学术
皮尔 N 等人。健康大脑老化和认知障碍期间脑脊液免疫失调。细胞。 2022；185：5028–5039e5013。
文章 CAS PubMed PubMed Central Google Scholar

下载参考资料

DH 部分得到国家多发性硬化症协会研究补助金 RG-2111-38681（授予 DH）和布莱根妇女医院教师职业发展奖（授予 DH）的支持。

作者和单位

安·罗姆尼神经疾病中心，布莱根妇女医院，哈佛医学院，02115，波士顿，马萨诸塞州，美国
胡丹 & 霍华德·维纳

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DH 和 HLW 撰写了手稿。作者阅读并批准了最终手稿。

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