Multiple studies highlight the role of effector and regulatory CD4⁺T cells in the pathophysiology of Alzheimer’s disease, and foster low-dose IL-2 treatment which induces regulatory CD4⁺T (Treg) cells expansion and activation as a promising strategy for its treatment. However, studies demonstrating discrepant Treg functions in AD have been reported. In addition, a compromised immune system associated with aging may substantially impact on these processes. Here, we report that there is an altered balance of activity between Treg cells and IL-17-producing helper T (Th17) cells in periphery and brain of APP/PS1 mice along the disease progression. A dramatic loss of the healthy balance of activity between Treg and Th17 cells was found at the middle disease stage. While peripheral low-dose recombinant human IL-2 administration could selectively modulate the abundance of Treg cells and repair the imbalance between Treg and Th17 subsets at the middle disease stage. We further show that modulation of peripheral immune balance through low-dose IL-2 treatment reduces the neuro-inflammation and increases numbers of plaque-associated microglia, accompanied by marked reduction of Aβ plaque deposition and slower cognitive declines in APP/PS1 mice at the middle disease stage. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of the homeostasis of CD4⁺T cell subsets in Alzheimer’s disease at the middle disease stage.

Graphical Abstract

中文翻译：

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低剂量 IL-2 治疗通过修复阿尔茨海默病中期 Treg 细胞和 Th17 细胞之间的不平衡来挽救认知缺陷

^{多项研究强调了效应细胞和调节性 CD4 +} T 细胞在阿尔茨海默病病理生理学中的作用，并促进低剂量 IL-2 治疗诱导调节性 CD4 ⁺ T (Treg) 细胞扩增和激活，作为一种有前景的治疗策略。然而，已有研究表明 AD 中 Treg 功能存在差异。此外，与衰老相关的免疫系统受损可能会对这些过程产生重大影响。在此，我们报告称，随着疾病进展，APP/PS1 小鼠外周和大脑中的 Treg 细胞和产生 IL-17 的辅助 T (Th17) 细胞之间的活性平衡发生了变化。在疾病中期发现 Treg 细胞和 Th17 细胞之间的健康活性平衡急剧丧失。而外周低剂量重组人IL-2给药可以选择性调节Treg细胞的丰度，修复疾病中期Treg和Th17亚群之间的不平衡。我们进一步表明，通过低剂量 IL-2 治疗调节外周免疫平衡可减少神经炎症并增加斑块相关小胶质细胞的数量，同时伴随着 APP/PS1 小鼠 Aβ 斑块沉积的显着减少和认知能力下降的减缓。疾病中期。^{我们的研究强调了重新调整用途的 IL-2 在基于 CD4 +} T 细胞亚群稳态调节的创新免疫疗法中对阿尔茨海默氏病中期疾病的治疗潜力。

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