Low-dose IL-2 Treatment Rescues Cognitive Deficits by Repairing the Imbalance Between Treg and Th17 Cells at the Middle Alzheimer's Disease Stage.

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.