T-cell dysfunction and death in sepsis: a mechanistic review

Sepsis is a life-threatening syndrome of multi-organ dysfunction caused by a dysregulated host response to infection. Despite advances in supportive care, the underlying immunopathological mechanisms remain incompletely understood. A hallmark of sepsis is immunoparalysis, characterized by an early hyperinflammatory phase followed by sustained immunosuppression, predisposing patients to secondary infections and adverse outcomes. A central feature of this process is profound lymphopenia accompanied by impaired T-cell effector function. This review synthesizes current evidence on T-cell perturbations during sepsis, encompassing numerical depletion, persistent upregulation of inhibitory immune checkpoints, and dysregulated cytokine signaling. We further highlight emerging evidence on four major modes of T-cell loss and dysfunction: apoptosis, autophagy dysfunction, pyroptosis, and ferroptosis, and discuss their integrated impact on immune competence. A deeper understanding of the mechanisms underlying T-cell death may facilitate the development of targeted immunomodulatory strategies and adjunctive therapies for sepsis, an area where effective interventions remain limited.