Western Diet Dampens T Regulatory Cell Function to Fuel Hepatic Inflammation in Metabolic Dysfunction-Associated Steatotic Liver Disease

The immunosuppressive T regulatory cells (Tregs) regulate immune responses and maintain immune homeostasis, yet their functions in metabolic dysfunction-associated steatotic liver disease (MASLD) remain controversial. Here we report increased accumulation of Tregs and effector T cells within the liver parenchyma of mice fed a Western diet (WD). This pattern was also observed in MASH patients, where an increase in intrahepatic Tregs was noted. In the absence of adaptive immune cells in <i>Rag1</i> KO mice, WD promoted accumulation of intrahepatic neutrophils and macrophages and exacerbated hepatic inflammation and fibrosis. Similarly, targeted Treg depletion exacerbated WD-induced hepatic inflammation and fibrosis. In Treg-depleted mice, hepatic injury was associated with increased accumulation of neutrophils, macrophages, and activated T cells in the liver. Conversely, induction of Treg numbers using recombinant IL2/αIL2 mAb cocktail reduced hepatic steatosis, inflammation, and fibrosis in WD-fed mice. Analysis of intrahepatic Tregs from WD-fed mice revealed a phenotypic signature of impaired Treg function in MASLD. Ex vivo functional studies showed that glucose and palmitate, but not fructose, impaired the immunosuppressive ability of Treg cells. The findings indicate that the liver microenvironment in MASLD impairs the ability of Tregs to suppress effector immune cell activation, thus perpetuating chronic inflammation and driving MASLD progression.