The dura sinus-resident immune cells can influence the process of central neural system (CNS) diseases by communicating with central nerve cells. In clinical, Tregs are also frequently impaired in depression. However, the significance of this relationship remains unknown. In the present study, we found a significant increase in dural Treg populations in mouse models of depression, whereas depleting them by neutralizing antibodies injection could exacerbate depressive phenotypes. Through RNA sequencing, we identified that the antidepressant effects of dural Tregs are at least in part through the production of amphiregulin, increasing the expression of its receptor EGFR in medial prefrontal cortex (mPFC) pyramidal neurons. Furthermore, dural Tregs expressed high levels of ST2, and their expansion in depressed mice depended on astrocyte-derived IL33 secretion. Our study shows that dural Treg signaling can be enhanced by treatment with fluoxetine, highlighting that dural Tregs can be utilized as a potential target cell in major depressive disorder (MDD).