GPR82-mediated activation of TGF-β/SMAD signaling contributes to CD8+ T cell dysfunction in HBV-ACLF.

Patients with acute-on-chronic liver failure (ACLF) have severe CD8+ T cell dysfunction. This study examined G protein-coupled receptor 82 (GPR82) in CD8+ T cell exhaustion in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Using GEO analysis, clinical samples, GPR82 manipulation, transforming growth factor beta (TGF-β)/SMAD intervention, dual-luciferase assays, and a mouse hepatitis virus strain 3 (MHV-3) mouse model, we found GPR82 overexpression in ACLF liver and HBV-ACLF CD8+ T cells, correlating with T cell exhaustion. GPR82 knockdown enhanced CD8+ T cell function, while overexpression had opposite effects. Mechanistically, lysophosphatidylcholine (LysoPC) upregulated GPR82 transcription via TGF-β/SMAD1, and elevated GPR82 further activated TGF-β/SMAD, forming a positive feedback loop. In vivo, GPR82 knockdown partially restored CD8+ T cell function and alleviated liver injury in the MHV-3 mouse model. These findings indicate GPR82 promotes CD8+ T cell exhaustion via TGF-β/SMAD, and the LysoPC-GPR82 loop offers insight into ACLF immune dysfunction, suggesting GPR82 as a potential biomarker and therapeutic target.