Protective role of PCED1B-expressing naive CD4+ T cells in sepsis

BACKGROUND: Sepsis is a global health challenge associated with high morbidity and mortality rates. Early diagnosis and treatment are challenging because of the limited understanding of its underlying mechanisms. This study aimed to identify effective biomarkers for diagnosing and treating sepsis through an integrated multi-method approach. METHODS: Publicly available single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq datasets were analyzed for naive CD4 + T cell-specific genes. Based on these hub genes, Mendelian randomization (MR) analysis, followed by the MR-Bayesian model averaging (MR-BMA) algorithm, was implemented to explore the causality between these genes and sepsis. In addition, single-cell-type expression analysis, cell-cell communication detection, metabonomic evaluation, clinical samples, and both in vivo and in vitro studies were conducted to unveil the underlying mechanisms of potential therapeutic targets. RESULTS: scRNA-seq revealed significant depletion of naive CD4 + T cells in sepsis, identifying 33 key genes. Both MR and MR-BMA analyses confirmed that elevated proportion of naive CD4 + T cell in total CD4 + T cells were related to sepsis occurrence (odds ratio [OR] = 0.90, 95% confidence interval [CI], 0.83-0.97, P = 0.007) and 28-day mortality associated with sepsis (OR = 0.75, 95% CI, 0.64-0.88, P