['CD56(+) T cells are abundant in liver and play an important role in defense against viral infections. However, the role of CD56(+) T cells in control of hepatitis C virus (HCV) infection remains to be determined. We investigated the noncytolytic anti-HCV activity of primary CD56(+) T cells in human hepatocytes. When HCV Japanese fulminant hepatitis-1 (JFH-1)-infected hepatocytes were co-cultured with CD56(+) T cells or incubated in media conditioned with CD56(+) T cell culture supernatants (SN), HCV infectivity and replication were significantly inhibited. The antibodies to interferon (IFN)-gamma or IFN-gamma receptor could largely block CD56(+) T cell-mediated anti-HCV activity. Investigation of mechanism(s) responsible for CD56(+) T cell-mediated noncytolytic anti-HCV activity showed that CD56(+) T SN activated the multiple elements of janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and enhanced the expression of IFN regulatory factors (IRFs) 1, 3, 7, 8, and 9, resulting in the induction of endogenous IFN-alpha/beta expression in hepatocytes. Moreover, CD56(+) T SN treatment inhibited the expression of HCV-supportive micro RNA (miRNA)-122 and enhanced the levels of anti-HCV miRNA-196a in human hepatocytes.'] Do cD56+ T cells inhibit hepatitis C virus replication in human hepatocytes?