Hetereogenity of liver Treg in the CDAHFD model of MASH
Metabolic-dysfunction–associated steatohepatitis (MASH) is a chronic liver disease driven by the confluence of metabolic stress and destructive hepatic inflammation. The immunoregulatory mechanisms that temper this process remain poorly understood. Exploiting a complementary pair of murine models and published single-cell RNA-sequencing (scRNA-seq) datasets from human liver, we uncovered a critical protective role for Foxp3+CD4+ regulatory T cells (Tregs) in MASH. Tregs progressively accumulated in the diseased liver, adopting an activated, nonlymphoid-tissue phenotype marked by the expression of Peroxisome Proliferator-Activated Receptor Gamma (PPAR?) and a reparative transcriptional program. Punctual ablation of Tregs during established MASH unleashed a catastrophic inflammatory cascade, including exaggerated T-helper (Th)1, Th2 and Th17 responses, expansion of a pathogenic CD8+ T cell population, and hepatocellular injury. Concomitantly, Treg deficiency disrupted key metabolic pathways in the liver, accelerating disease progression. These findings establish Tregs as non-redundant custodians of both immunologic and metabolic homeostasis in the liver, highlighting their promise as targets for temporally tuned immunoregulatory therapies in metabolic liver disease. Overall design: We investigated the transcriptional heterogeneity of liver regulatory T cells (Tregs) 8 days after feeding with CDAHFD or control diet via single-cell RNA sequencing (scRNA-seq). Tregs from livers of Foxp3Gfp mice ere sorted by flow cytometry and encapsulated using the Chromium Single Cell 3' v2 platform.