Transcriptional profiles of CD4+ and CD8+ T cells in major depressive disorder

Abstract Major depressive disorder (MDD) has been associated with peripheral immune alterations, but transcriptional changes within the major T cell lineages remain poorly characterized. We performed bulk RNA sequencing of magnetically-enriched CD4+ and CD8+ T cell fractions from a cohort comprising 81 individuals with MDD and 48 healthy controls (HCs). Differential expression was assessed for protein-coding genes and long noncoding RNAs (lncRNAs), canonical T cell receptor (TCR)-segment transcripts were examined separately, and Ingenuity Pathway Analysis was used to characterize associated molecular pathways and upstream regulators. In CD4-enriched cells, 202 protein-coding genes and lncRNAs met a false discovery rate threshold of < 0.05, whereas no gene met this threshold in CD8-enriched cells. Twenty-one canonical TCR-segment transcripts, predominantly TRAJ genes, were increased in MDD. Pathway analysis implicated broad transcription- and chromatin-regulatory programs. Exploratory sex-stratified analyses identified a broader CD4+ signature in males, comprising 487 differentially expressed genes and including reduced cytotoxic/natural killer-like and major histocompatibility complex class I antigen-processing programs, together with increased TRAJ transcript abundance. These findings identify an MDD-associated peripheral transcriptional signature detected primarily in CD4-enriched cell fractions and characterized by distributed regulatory-state and TCR-segment changes. Together, this dataset provides a cell-type-resolved foundation for future studies examining the clinical relevance and functional consequences of CD4+ T cell transcriptional alterations in MDD.