Neutrophil-Derived Arg1 Impairs CD8⁺ T Cell Activity in Sepsis Through mTOR-Mediated Mitochondrial Dysfunction

This research aimed to elucidate the contribution of Arginase 1 (Arg1) to pediatric sepsis progression, specifically impacting the effector functions of CD8⁺ T lymphocytes.

Arg1 expression was assessed in venous blood from pediatric sepsis patients (n = 21) and healthy volunteers (n = 21). Pharmacological inhibition of Arg1 was achieved using Nor-NOHA in both sepsis patients-derived neutrophils and LPS-stimulated healthy neutrophils, followed by co-culture with CD8⁺ T cells. Sepsis-derived neutrophils were also treated with hArg1 monoclonal antibody (mAb). CD8⁺ T cell viability, exhaustion markers (PD-1/TIM-3), mitochondrial membrane potential, ATP production, autophagy, and inflammatory cytokine secretion were systematically evaluated.

Arg1 expression was markedly upregulated in sepsis patients correlated positively with neutrophil counts but negatively with CD8⁺ T cell numbers and mitochondrial function. Strikingly, CD8⁺ T cells from Arg1-high patients exhibited increased PD-1⁺TIM-3⁺ double-positive populations. Both Nor-NOHA-mediated Arg1 inhibition and hArg1-mAb neutralization significantly restored CD8⁺ T cell mitochondrial membrane potential (MMP), ATP production, and effector cytokine secretion, while concurrently reducing PD-1/TIM-3 expression.

Our findings indicate that overexpression of Arg1 derived from neutrophils leads to a highly inflammatory response suggesting that Arg1 is a potential prognostic biomarker and therapeutic target in pediatric sepsis.