Exosomal miR-484 impairs CD8 ⁺ T cell homeostasis in sepsis through the YPEL1/Cyclin E axis

Sepsis induces profound CD8 ⁺ T cell dysfunction, contributing to immunosuppression and poor outcomes. Exosomes mediate intercellular communication during sepsis, but the role of exosomal microRNAs in regulating CD8 ⁺ T cell homeostasis remains unclear. Sepsis patients and healthy controls are prospectively enrolled to investigate plasma exosomes and CD8 ⁺ T cell responses. Exosomes from sepsis patients (SE) promote CD8 ⁺ effector differentiation and dysregulate cell cycle progression compared to those from healthy donors (HE). miRNA sequencing identifies miR-484 as the most upregulated miRNA in SE. Functionally, SE-derived miR-484 suppresses YPEL1 expression in CD8 ⁺ T cells, leading to increased Cyclin E levels and aberrant cell cycle distribution. Inhibition of miR-484 restores YPEL1 and normalizes Cyclin E expression, which is associated with a reversal of the sepsis exosome-induced bias toward CD8 ⁺ effector differentiation. Our findings reveal that exosomal miR-484 impairs CD8 ⁺ T cell homeostasis in sepsis by targeting the YPEL1/Cyclin E pathway, highlighting a potential mechanism for immune dysregulation and a target for intervention.