Regulatory T and activated T cells in the chronic unpredictable mild stress mice: sex differences and effects of treatments

Background: Major depressive disorder (MDD) is associated with immune dysregulation, including T-cell activation and reduced regulatory T cells. Pharmacological treatments like fluoxetine, simvastatin, curcumin, and S-adenosylmethionine (SAMe) show promise in alleviating depressive symptoms, but their effects on immune responses are not fully understood. Methods: This study explored immune status in MDD using the chronic unpredictable mild stress (CUMS) mouse model. It examined how fluoxetine, simvastatin, curcumin, and SAMe affected immune responses and depressive behaviors. The study also investigated sex differences. Six groups, each with 12 mice (6 males and 6 females), were included: control, CUMS, and drug treatments. Male and female mice were housed separately in sex-specific cages throughout the experiment, with three mice per cage. Behavioral tests included sucrose preference, forced swimming, open field, and active avoidance. Immune cell markers were analyzed by flow cytometry. Results: CUMS mice showed immune imbalance, with Treg depletion (p = 0.047) and a higher CD154/CD152 ratio (p = 0.006). All treatments improved depressive-like behaviors (all p < 0.05), with SAMe normalizing the CD154/CD152 ratio (p = 0.009). Furthermore, female mice exhibited lower levels of Treg-related immune regulation and T-cell activation compared to males (both p < 0.001), along with a higher CD154/CD152 ratio (p = 0.008). Conclusion: This study highlights that curcumin, simvastatin, fluoxetine, and SAMe alleviate depressive-like behaviors, while SAMe also reduces the CD154/CD152 ratio. These findings reveal marked sex differences in T-cell activation and immune regulation, highlighting the importance of considering sex as a biological variable in CUMS research.