The Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication Through Production of IFN-γ and TNF-⍺

Abstract

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can be programmed to be HBV-specific and to infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model of HBV infection. A hydrodynamic injection of an HBV expression plasmid, pAAV/HBV1.2, into the liver induced HBV replication efficiently in mice. We show that adoptive transfer of HBV Ag-specific iPSC-CTLs greatly suppressed the HBV replication in the liver and blood in the animal model and prevented the HBV surface Ag expression on hepatocytes. We further demonstrate that the adoptive transfer significantly increased the migration of CD8+ T cells and the production of the antiviral cytokines (IFN-γ, TNF-α) in the liver. Moreover, using neutralizing antibody to IFN-r or/and TNF-a dramatically dismissed the suppression of the HBV replication mediated by the HBV Ag-specific iPSC-CTLs. These results indicate that the stem cell-derived tissue-associated CTLs can robustly accumulate in the liver and suppress the HBV replication through producing the antiviral cytokines IFN-r and TNF-a.