T cell exhaustion in sepsis: mechanisms, biomarkers, and immune-reversal strategies

Abstract

Sepsis is increasingly recognized as a dynamic immune disorder in which early hyperinflammation may coexist with or progress to profound immunosuppression. T-cell exhaustion is a central feature of this immune paralysis and is characterized by lymphopenia, impaired proliferation, reduced effector cytokine production, inhibitory receptor upregulation, metabolic dysfunction, and defective antibacterial immunity. Recent studies have expanded the mechanistic landscape of sepsis-induced T-cell exhaustion beyond the classical PD-1/PD-L1 axis. TIGIT-mediated suppression of CD4+ T-cell immunity, extracellular vesicle-associated PD-L1, TOX-independent exhaustion-like programming, dysregulated IL-17 production, mitochondrial dysfunction, and reduced glutaminase expression in CD4+ T cells have emerged as important mechanisms. These findings indicate that septic T-cell exhaustion is not a direct replica of exhaustion in cancer or chronic viral infection, but a context-dependent and potentially reversible immune dysfunction state. Biomarkers such as PD-1+CD3+ T cells, soluble PD-1/PD-L1, IL-7, TIGIT, EV-PD-L1, and GLS may support patient stratification and dynamic immune monitoring. Immune-reversal strategies, including PD-1/PD-L1 blockade, TIGIT inhibition, IL-7-based restoration, and metabolic reprogramming, require precise timing and individualized selection to restore host defense without aggravating inflammatory organ injury.