Precise immunomodulation by mesenchymal stem cells mitigates hepatitis B virus-specific CD8⁺ T cell-mediated acute liver injury without compromising viral clearance.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a high mortality rate. Although mesenchymal stem cell (MSC) therapy markedly improves liver function and survival in patients with HBV-ACLF, it remains unclear whether the immunomodulatory effects of MSCs suppress antiviral CD8⁺ T cell function and trigger HBV reactivation. Here, we developed a novel in vitro HBV-specific CD8⁺ T cell-mediated acute liver injury organoid model, which was co-cultured with either menstrual blood-derived MSCs (MenSCs) or umbilical cord-derived MSCs (UC-MSCs). We found that both MenSCs and UC-MSCs coordinate liver repair and antiviral immunity through precise immunomodulation, primarily via paracrine signaling. Both MSC types significantly downregulated pro-inflammatory (IFN-γ, TNF-α, IL-8, and CXCL10) and apoptosis-related genes (FasL and CASP7), while promoting hepatic regeneration through IL-6 and HGF upregulation, without compromising CD8⁺ T cell-mediated HBV clearance. This study provides critical insights into the safety of MSC therapy for HBV-ACLF.