The Homeostasis and Heterogeneity of Regulatory T Cells in Sepsis

Abstract

Sepsis poses a critical threat to global health, mainly due to the disruption of immune homeostasis, which critically influences both early death and long-term adverse outcomes. Current evidence shows that regulatory T (Treg) cells—key mediators of adaptive immunity—play an essential role in maintaining immunological balance during the development of sepsis. During the initial hyperinflammatory phase, Treg cells actively suppress excessive inflammation, reducing tissue damage. Paradoxically, in the subsequent immunosuppressive phase, expanded Treg populations may worsen immunosuppression by inhibiting effector cell function, ultimately leading to poorer clinical outcomes. Recent research has identified novel Treg-specific biomarkers in sepsis and explained how the septic environment affects Treg numbers and function through various signalling pathways. This review combines current understanding of the phenotypic features and roles of Treg cells in sepsis, examines the regulatory mechanisms controlling Treg dynamics within the inflammatory setting, and explores therapeutic strategies targeting Treg cells across different immune phases, emphasizing both existing challenges and future directions.