Abstract
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.
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Some or all data or models generated or used during the study are available from the corresponding author by request.
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Funding
This work was supported by Open Fund Projects of Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases (No.PT022102), Youth Innovation Team of Shandong Provincial Department of Education (No. 2022KJ125), Shandong Provincial Natural Science Foundation of China (No. ZR2022MH051), National Natural Science Foundation of China (No.82071792 and No.81701042), Science, Education and Industry Integration Innovation Pilot Project from Qilu University of Technology (Shandong Academy of Sciences) (Grant No. 2022JBZ02-04) and Industry-University-Research Collaborative Innovation Fund from Qilu University of Technology (Shandong Academy of Sciences) (No.2020-CXY16).
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C.L., D.Y. and L.Y. designed research; L.Y., L.X., H.Z., Y.Z., Y.B.W., J.H.F, L.C., R.T. and J.F. performed research; L.Y., L.X., R.T. and J.F. contributed expertise in behavioral studies; C.Y., L.X., H.Z., Y.Z., Y.B.W., J.H.F, and L.C. analyzed data; C.L. and L.Y. wrote the paper.
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All animal experiments were carried out under a Shandong Analysis and Test Center Laboratory Animal Welfare Ethics Review Committee approved license (Approval No. ECAESDATC-2020–016) and in accordance with the UK Animals (Scientific Procedures) Act, 1986 Amendment Regulations (SI 2012/3039). All efforts were made to minimize the number of animals used and their suffering.
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Yuan, L., Xie, L., Zhang, H. et al. Low-dose IL-2 Treatment Rescues Cognitive Deficits by Repairing the Imbalance Between Treg and Th17 Cells at the Middle Alzheimer’s Disease Stage. J Neuroimmune Pharmacol 18, 674–689 (2023). https://doi.org/10.1007/s11481-023-10090-x
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DOI: https://doi.org/10.1007/s11481-023-10090-x