From model to man: Understanding Tregs' dual role in MASLD

Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) affects around 30% of the world's population and is often associated with metabolic conditions such as obesity, diabetes and hypertension. Approximately 10-20% of metabolic dysfunction-associated steatotic liver disease cases progress to metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the risk of liver cancer. While intrahepatic immune responses involving CD4+ and CD8+ T cells are potential therapeutic targets, their role in the pathogenesis of MASH is not fully understood. Regulatory T cells (Tregs), whose involvement has been controversial, require further investigation.

In this study, we investigated the impact of adaptive immunity on MASH using a high-fat/high-carbohydrate diet (HF-HCD) model in wild-type and Rag2-deficient C57BL/6 mice, supplemented with human liver samples.

Our results showed that HF-HCD induced glucose intolerance and MASH, independent of adaptive immunity. Surprisingly, HF-HCD increased intrahepatic Treg numbers and the Treg/Teff ratio but did not alleviate the disease; instead, this increase correlated with greater disease severity. With progressing metabolic inflammation, an increased proportion of Tregs also expressed IL-17, which correlated with more severe liver pathology.

The observed expansion of Tregs and the resulting increase in the Treg/Teff ratio did not protect against MASH but correlated with more severe disease in both mice and humans, consistent with a pro-inflammatory shift towards IL-17-producing (T_H17-skewed) cells. These findings highlight the complex role of adaptive immunity in MASH progression and provide potential targets for future immunomodulatory therapies.

Diet-induced steatohepatitis can develop without adaptive immunity, yet IL-17A-expressing Foxp3⁺ T regulatory cells (Tregs) and CD8⁺ T cells markedly amplify hepatocellular injury and fibrosis. By separating initiating (macrophage-driven) from amplifying (adaptive) immune signals, our study refines current pathogenic models and provides hepatologists and immunologists with stage-specific therapeutic targets. For clinicians and trial designers, the data indicate that stabilizing Tregs or selectively dampening pro-inflammatory T-cell subsets could complement metabolic interventions in metabolic dysfunction-associated steatotic liver disease/steatohepatitis, whereas indiscriminate Treg expansion might be counter-productive. Because the conclusions are drawn from a murine model, translation to humans will require validation in patient-derived tissues and non-invasive immune biomarkers.