Regulatory T-cell Notch4 expression correlates with mortality in hospitalized COVID-19 patients

Severe COVID-19 is characterized by profound immune dysregulation, yet the mechanisms distinguishing fatal from non-fatal outcomes remain incompletely understood. Regulatory T (Treg) cells have been shown to play a central role in regulating immune responses and promoting tissue repair. In this study, we investigate the expression of Notch4 on peripheral circulating Treg cells in 169 hospitalized COVID-19 patients and evaluate its association with clinical outcomes.

Our analysis divulges that Notch4 expression on Treg cells correlates significantly with death in patients after six weeks of intensive care unit (ICU) admission, correlating with hypoxia, immunosuppression, and multiple organ failure. Unlike early-phase inflammatory cytokines such as IL-6, IL-8, and IL-10-whose upregulation was observed during the first two weeks-Notch4 expression emerges as a late marker, specifically distinguishing patients who eventually succumb to the disease. Similar to earlier reports, deeper immune profiling of Regulatory cells identified a short of both reg and T follicular regulatory (Tfr) cells in deceased patients toward a proinflammatory profile, suggesting phenotypic reprogramming. In our previous studies, Notch4 expression was strongly associated with decreased regulatory capacity and increased immune activation. Our results indicate that persistent Notch4+ Treg signatures, particularly after 6 weeks of ICU admission, serve as critical markers of mortality in COVID-19.

Notch4 can be used as a viable therapeutic target to restore immune homeostasis in critically ill patients. Further studies are still needed to understand the role of Treg cell Notch4 expression in other viral acute respiratory distress syndromes (ARDS).