CD4+效应 T 细胞加速了小鼠的阿尔茨海默病进程。

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. METHODS: In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA (MHCII-IA-KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. RESULTS: The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. CONCLUSIONS: These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.

背景：阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是病理性沉积错误折叠的自我蛋白淀粉样β（Aβ），这反过来又促进了 tau 聚集和神经退行性变。神经炎症被认为是由先天小胶质细胞激活引起的关键疾病驱动因素。最近，人们发现适应性免疫改变早在疾病发生之前就已经发生，并持续存在于整个疾病过程中。这些改变是如何发生的，以及它们是否可以被利用来阻止疾病进展尚不清楚。我们假设自身抗原会诱导自身反应性效应 T 细胞（Teffs），从而驱动促炎和神经破坏性免疫，导致认知障碍。在这里，我们研究了效应免疫的作用及其如何影响 AD 动物模型中的细胞水平疾病病理生物学。

方法：在本报告中，我们开发并表征了克隆的淀粉样β（Aβ）反应性 1 型辅助性 T 细胞（Th1）和 17 型 Th（Th17）细胞系，以研究它们在 AD 发病机制中的作用。使用流式细胞术、免疫印迹染色和 Aβ T 细胞表位负载的单倍型匹配主要组织相容性复合体 II IA（MHCII-IA-KLVFFAEDVGSNKGA）四聚体结合，证实了 Aβ 特异性 Th1 和 Th17 克隆的细胞表型和抗原特异性。将 Aβ-Th1 和 Aβ-Th17 克隆过继转移到表达嵌合小鼠/人淀粉样前体蛋白和突变人早老素 1 的 APP/PS1 双转基因小鼠中，并评估小鼠的记忆障碍。最后，采集血液、脾脏、淋巴结和大脑进行免疫、生化和组织学分析。

结果：增殖的 Aβ-Th1 和 Aβ-Th17 克隆被证实稳定且寿命长。用 Aβ 反应性 Teffs 治疗 APP/PS1 小鼠加速了记忆障碍和全身炎症，增加了淀粉样蛋白负荷，升高了小胶质细胞激活，并加剧了神经炎症。Th1 和 Th17 Aβ 反应性 Teffs 通过下调外周和中枢神经系统中的抗炎和免疫抑制调节性 T 细胞（Tregs）来加重 AD 病理。

结论：这些结果强调了 CD4+Teffs 在 AD 进展中的重要病理作用。我们假设，与疾病相关的效应 T 细胞免疫反应可以得到控制。一种解决方案是通过 Aβ 反应性 Tregs。