IFN-? production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells.

ABSTRACT: Interferon-? (IFN-?), a cytokine produced by activated natural killer cells (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-? induction in HCV-infection are not fully understood.We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected HuH7.5 (JFH-1/HuH7.5) cells.We found that PBMCs produced large amounts of IFN-? after co-culture with JFH-1/HuH7.5 cells. Using intracellular cytokine staining, we confirmed that NK cells and NKT cells (to a lesser extent) were the major IFN-? producers within PBMCs. Purified NK/NKT cells did not produce IFN-? in response to JFH-1/HuH7.5 cells and depletion of accessory (HLA-DR(+)) cells prevented IFN-? induction in PBMCs. Through selective cell depletion of dendritic cells or monocytes from PBMCs, we determined that plasmacytoid dendritic cells (pDCs) were indispensable for NK-IFN-? induction and the presence of monocytes was needed for maximal NK-IFN-? induction. We further revealed that NK-IFN-? induction depended on pDC-derived IFN-? while other IFN-? inducing cytokines, IL-12, and IL-18, played minimal roles. Close contact between JFH-1/HuH7.5 cells and NK cells was required for IFN-? production and monocyte-derived IL-15 significantly augmented IFN-? induction.We discovered a novel mechanism where NK cells interact with pDCs and monocytes, efficiently producing IFN-? in response to HCV-infected cells. This indicates that co-operation between NK cells and accessory cells is critical for IFN-? production and regulation of immunity during HCV infection.

SUBMITTER: Zhang S 

PROVIDER: S-EPMC3760030 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature