Serum amyloid A1–induced intrahepatic regulatory T-cell dysfunction drives autoimmune hepatitis progression

BACKGROUND AND AIMS: Treatment of autoimmune hepatitis (AIH) remains challenging and primarily relies on corticosteroid therapy. Regulatory T cells (Tregs), essential for maintaining immune homeostasis and preventing various autoimmune diseases, present a potential therapeutic target for AIH. However, the role of Tregs in AIH pathogenesis remains unclear. APPROACH AND RESULTS: In a well-established AIH model induced by hydrodynamic transfection of cytochrome P450 2D6 (CYP2D6) plasmid into mouse liver, Tregs were found to increase in number as the disease progressed. Despite the increased hepatic Treg presence, the proportions of effector T cells also rose, contributing to disease progression. Systemic Treg depletion using FoxP3-DTR/eGFP mice exacerbated AIH progression, while adoptive Treg transfer failed to alleviate liver inflammation and fibrosis, highlighting intrahepatic Treg dysfunction. Single-cell RNA sequencing of hepatic Tregs using the 10× Genomics platform identified impaired suppressive function and a shift toward proinflammatory phenotypes, contrasting with enhanced suppressive capacity observed in peripheral Tregs. This intrahepatic Treg dysfunction was associated with elevated hepatic serum amyloid A1 (SAA1) levels, which impaired Tregs through toll-like receptor 2. Liver-specific AAV8-mediated shSAA1 therapy restored Treg function and ameliorated AIH symptoms, while the adoptive transfer of Tregs lacking toll-like receptor 2 significantly improved disease outcomes. CONCLUSIONS: Intrahepatic Tregs exhibit a diminished suppressive phenotype and an enhanced effector phenotype, failing to control the escalating inflammation in AIH. AIH treatment should not only focus on increasing Treg numbers but also on restoring their functional capacity.