Adaptive immune dysregulation in depression: Cross-species evidence of CD4+ T cell dysfunction and pro-inflammatory pathway activation

The association between central adaptive immunity and depression remains highly debated. In this study, we systematically assessed the role of adaptive immune mechanisms in depression using a mouse model of chronic unpredictable mild stress (CUMS) and the peripheral blood of patients with depression. The behavioral results demonstrated that the CUMS mice exhibited typical depression-like behaviors. Subsequent transcriptomic analysis of the hippocampus identified 203 differentially expressed genes (DEGs), of which CD4 expression was significantly downregulated. Furthermore, DEGs were enriched in the tumor necrosis factor (TNF) and interleukin (IL)-17 signaling pathways. Validation experiments further corroborated the hypothesis that the CD4 gene in the hippocampal region of CUMS mice was reduced in parallel with the protein levels. Immunocorrelation assays revealed a decrease in intercellular cell adhesion molecule-1 expression in the hippocampus, along with an increase in vascular cell adhesion molecule-1 expression. These changes were accompanied by cytokine level disruption in CUMS mice. A total of 391 DEGs were identified in the transcriptome sequencing of peripheral blood CD4⁺T cells from patients with depression using the Gene Expression Omnibus database. These DEGs were significantly associated with the PI3K-AKT, IL-17, and TNF signaling pathways. Immune checkpoint analysis revealed elevated PDCD1 and decreased TIGIT expression in CD4⁺T cells of the patients. The integration of animal models and clinical data revealed a convergent pattern of findings, indicating CD4⁺ T-cell dysfunction and the activation of pro-inflammatory pathways as immune features shared across species in depression. This provides a novel rationale for targeted immunomodulatory treatment of depression.