Accumulation of regulatory T cells correlate with severity of NASH in patients and mice

Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of the world's population. NAFLD is associated with common metabolic comorbidities such as obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidaemia, hypertension and metabolic syndrome and 10-20% of NAFLD patients develop non-alcoholic steatohepatitis (NASH), which can progress to hepatocellular carcinoma (HCC). Therefore, although the majority of NAFLD patients die from cardiovascular events rather than liver-related causes, NAFLD is an increasing cause of fatal disease worldwide.

Animal models should therefore mimic these disease conditions to advance our understanding of pathophysiology and new therapeutic interventions. A high-fat/high-carbohydrate diet, including fructose, is currently one of the best ways to induce a NASH phenotype in otherwise healthy inbred mouse strains. Furthermore, to prove the relevance of our experimental data we additionally retrospectively quantified the T cell compartment in liver biopsies and peripheral blood samples from NASH patients.

We analyzed the intrahepatic Treg response and the impact of therapeutic interventions that increase intrahepatic Treg numbers in experimental NASH with a strong activation and clonal expansion of intrahepatic T cells . Lobular accumulation of regulatory T cells increases with severity of NAFLD in humans. In association with increasing metabolic inflammation, Tregs differentiate into TH17-like cells, promoting disease exacerbation.

In conclusion, T cells are the drivers of metabolic inflammation. Nonetheless, Tregs are not able to control this inflammation but promote disease exacerbation by converting to TH17-like cells.

Publication History

Article published online:
23 January 2024