Regulatory T-cell and neutrophil extracellular traps interaction contributes to the development of immunosuppression in sepsis

The excessive formation and release of neutrophil extracellular traps (NETs) in sepsis may represent a substantial mechanism contributing to multi-organ damage, which is associated with a poorer prognosis. However, the precise role of NETs in mediating the transition from innate immunity to adaptive immunity during the progression of inflammation and sepsis remains incompletely elucidated. In this study, we provide evidence that, despite a reduction in the number of CD4+ T-cells in the late stage of sepsis, there is a notable upregulation in the proportion of regulatory T-cells (Tregs). Mechanistically, we have identified that NETs can induce metabolic reprogramming of naïve CD4+ T-cells through the Akt-mTOR-SREBP2 pathway, resulting in enhanced Cholesterol metabolism, thereby promoting their conversion into Tregs and augmenting their functional capacity. Collectively, our findings highlight the potential therapeutic strategy of targeting intracellular Cholesterol normalization for the management of immunosuppressed patients with sepsis.

Adaptive immunity; Immunology; Immunotherapy; Inflammation; T cell development.