IL-6 signaling drives treg dysfunction and pathogenic Th1-like polarization in major depressive disorder

Abstract

Major depressive disorder (MDD) is pathologically associated with inflammatory-immune dysregulation. While regulatory T cells (Tregs) are essential for immune homeostasis, clinical evidence have reported paradoxical dynamics (deficiency vs. expansion) of peripheral Tregs in MDD patients. The plasticity of Tregs and microenvironmental reprogramming mechanisms remain elusive, highlighting the need for pathology-driven biomarkers and targeted interventions. In this study, we integrated mass cytometry (CyTOF; n = 37), single-cell RNA/T cell receptor sequencing ( n = 10), and flow cytometry ( n = 123) to systematically profile Tregs in MDD. Functional assays were conducted to evaluate suppressive capacity, interleukin-6/interferon-γ (IL-6/IFN-γ)-driven plasticity, and diagnostic utility via receiver operating characteristic (ROC) analysis. Results showed that MDD patients exhibit significant peripheral immune dysregulation, notably expanded peripheral Tregs (1.2-fold increase, p = 0.001). Single-cell analysis revealed that these were predominantly T-bet + Th1-like subpopulations (1.5-fold increase, p = 0.01) displaying mitochondrial dysfunction, elevated IFN-γ response (NES = 1.51), and impaired suppression (16.7 vs. 62.8% inhibition, p < 0.001). IL-6 signaling drove this aberrant differentiation, and IL-6 blockade reversed the inflammatory phenotype (1.8-fold reduction, p < 0.001). Clinically, T-bet + Th1-like Tregs effectively discriminated drug-naïve MDD patients (area under the curve [AUC] = 0.776, 95% confience interval (CI): 0.668–0.884) and correlated with symptom severity (HAMD score: r = 0.49, p < 0.001). These findings demonstrate that MDD-associated IL-6-driven Th1-like Treg polarization underlies MDD immunopathology, linking metabolic dysregulation with inflammatory conversion, and positions this subset as dual diagnostic biomarkers and therapeutic targets for modulating the IL-6/IFN-γ axis in depression.