T cell immunometabolic dysfunction in a mouse model of cecal ligation and puncture-induced sepsis

T lymphocyte dysfunction is closely associated with immunosuppression in sepsis, whereas the underlying mechanisms are not fully understood.

In this study, we established a mouse model of cecal ligation and puncture (CLP)-induced sepsis and observed immunometabolic alterations in splenic T cells. Serum energy metabolites related to glycolysis and the tricarboxylic acid (TCA) cycle were imbalanced. Splenic T cells from septic mice showed a shift in subset distribution, with decreased naïve T cells and increased effector populations, along with concurrent activation and exhaustion phenotypes. Notably, mitochondrial mass and mitochondrial membrane potential were significantly diminished in both CD4⁺ and CD8⁺ T cell, correlated with increased programmed cell death protein 1 (PD-1) expression. Transmission electron microscopy further confirmed mitochondrial morphological alterations in CLP-derived CD3⁺ T cells. Furthermore, seahorse assays demonstrated impaired metabolic reprogramming capacity in activated CLP splenic CD3⁺ T cells, with suppressed glycolytic and oxidative phosphorylation responses. This impairment was coupled with reduced fold-increases in mitochondrial mass and mitochondrial membrane potential levels upon activation in both CD4⁺ and CD8⁺ T cell compared to controls. Clinically, peripheral T cells from septic patients showed elevated CD69 and PD-1 expression, a significant increase in CD39 and a decrease in CD73, increased mitochondrial mass and decreased mitochondrial membrane potential, particularly in those with septic shock.

Our findings provide several layers of T cell dysfunction in sepsis, linking subset redistribution, an exhausted phenotype, mitochondrial impairment, and reduced proliferative capacity, suggesting that future therapeutic interventions aiming to reverse sepsis-induced immunosuppression may require a combinatorial approach.