IL-2-mediated Treg cells recruitment regulates neuroimmune crosstalk to promote hippocampal neurogenesis in depressive mice

Major depressive disorder (MDD) is a prevalent and debilitating neuropsychiatric disorder characterized by severe neuroinflammation and impaired hippocampal neurogenesis, yet effective clinical treatments remain limited. Accumulating evidence indicates that adaptive immune dysfunction may implicated in depressive pathogenesis, and CD4 + FOXP3+ regulatory T cells (Tregs) play vital roles in maintaining central immune homeostasis. However, the precise mechanism by which Tregs regulate depression remains poorly defined. In this study, we verified that multiple stress-induced depression mouse models exhibited excessive neuroinflammation and reduced hippocampal dentate gyrus (DG) neurogenesis, accompanied with downregulated expression of amphiregulin (AREG). More importantly, we found low-dose interleukin-2 (IL-2) treatment significantly recruited hippocampal Treg cells populations, alleviated neuroinflammation, restored impaired neurogenesis and rescued depressive-like and anxious-like behaviors. Moreover, IL-2-induced Treg cells recruitment upregulated AREG expression. Conversely, pharmacological inhibition of epidermal growth factor receptor (EGFR), he downstream receptor of AREG, effectively attenuated the antidepressant and pro-neurogenic effects of IL-2. Collectively, these findings demonstrate that IL-2 ameliorates depression-like deficits by regulating the AREG-EGFR signaling axis which linking Treg cells to neural stem cells. This study reveals a novel neuroimmunological mechanism underlying depressive pathogenesis and provides a promising immune-targeted strategy for antidepressant intervention.