Chronic stress disrupts Th17/Treg balance to induce depressive-like behaviors: Preclinical and clinical evidence.

Abstract

Chronic stress-induced immune dysregulation is implicated in depression, with the balance between T helper 17 (Th17) and regulatory T (Treg) cells being of particular interest. This study integrated preclinical and clinical evidence to investigate the transcriptional mechanisms of Th17/Treg imbalance and its behavioral correlates. In a rat model of chronic unpredictable mild stress (CUMS), we observed significant depressive-like behaviors, hippocampal histopathological damage, and a concurrent transcriptional shift in both the spleen and hippocampus, characterized by upregulation of Th17-associated factors (RORα, STAT3) and downregulation of Treg-related markers (FoxP3+, STAT5). The hippocampal RORα/FoxP3+ ratio strongly correlated with the severity of anhedonia and locomotor deficits. Clinically, this immune imbalance was validated in a cohort of depression patients (n = 52), who exhibited a significantly elevated peripheral Th17/Treg ratio compared to healthy controls (n = 40), which positively correlated with depression severity scores. These findings demonstrate that a conserved Th17/Treg transcriptional imbalance, across peripheral and central compartments, is a key pathological feature of depression, highlighting the potential of immunomodulatory strategies that restore this equilibrium as a novel therapeutic approach.