Natural Killer Cells in Hepatitis C Virus Infection: From Innate Immunity to Adaptive Immunity

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Natural killer (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is up-regulated on NK cells in patients with chronic hepatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as in nontransformed hepatocytes, but not in K562 cells, a classic NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing interferon-γ in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness toward K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which were restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity toward HCV-infected or transformed cells in chronic hepatitis C.

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Natural Killer Receptor Expression and Effector Cell Functions

We initially examined NK cell responsiveness in chronic hepatitis C.9 NK cells isolated from peripheral blood were cocultured for 24 hours with either Hep3B hepatoma cells or K562 cells, a classic NK-sensitive target, and subjected to flow cytometric analysis for IFN-γ production. NK cells from patients with chronic hepatitis C (HCV-NK), on exposure to K562 cells, produced IFN-γ at levels similar to those of NK cells isolated from healthy donors (N-NK). In contrast, HCV-NK cells did not produce

Impact of Natural Killer Cells on Adaptive Immunity

Originally, the NK cell was thought to be just an effector cell for killing unwanted cells. However, recent research has been shedding light on its role as a regulator for the subsequent adaptive immune responses. For example, there have been reports that NK cells activated DCs via a tumor necrosis factor–α–dependent mechanism,11 and that NK cells down-regulated an immune response by killing immature DCs.12 Immature DCs distributed into the peripheral organs such as the liver undergo maturation

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