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

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.

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.

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 <0.001). Notably, among the 33 hub genes, PC-esterase domain containing 1B ( PCED1B ) exhibited a strong causal association with 28-day mortality in patients with sepsis (OR = 0.64, 95% CI, 0.51-0.81, P <0.001), which was further validated by bulk RNA-seq analysis. PCED1B mediated the impact of proportion of naive CD4 + T cell in CD4 + T cell on sepsis-related mortality. In addition, clinical samples and both in vivo and in vitro experiments validated the elevated expression of PCED1B in naive CD4 + T cells derived from sepsis patients and mice. Mechanistic investigations revealed PCED1B+ CD4 + T cells may interact with monocytes/dendritic cells through the macrophage migration inhibitory factor (MIF)-(CD74 + CD44) axis, concurrently engaging with B cells/plasmablasts through the MIF-(CD74 + CXCR4) axis, thereby regulating multiple metabolic alterations in sepsis.

The interplay between PCED1B and naive CD4 + T cells, as revealed by this study, is instrumental in developing immunotherapeutic strategies for sepsis.