Control of HCV Infection by Natural Killer Cells and Macrophages

Abstract

Host defense against invading pathogens within the liver is dominated by innate immunity. Natural killer (NK) cells have been implicated at all stages of hepatitis C virus (HCV) infection, from providing innate protection to contributing to treatment-induced clearance. Decreased NK cell levels, altered NK cell subset distribution, activation marker expression, and functional polarization toward a cytolytic phenotype are hallmarks of chronic HCV infection. Interferon α (IFN-α) is a potent activator of NK cells; therefore, it is not surprising that NK cell activation has been identified as a key factor associated with sustained virological response (SVR) to IFN-α-based therapies. Understanding the role of NK cells, macrophages, and other innate immune cells post-SVR remains paramount for prevention of disease pathogenesis and progression. Novel strategies to treat liver disease may be aimed at targeting these cells.

Figure 1.

Natural killer receptors (NKRs). The activity of NK cells is determined by integration of signals arising from engagement of activating and inhibitory cell surface receptors. NKs respond to numerous cytokines and use several coreceptors not exclusively expressed on NKs. (KIR) killer immunoglobulin-like receptor, (HLA) human leukocyte antigen, (NKG2) natural killer group 2 D/A, (IFN-α) interferon α, (IL) interleukin, (DNAM) DNAX accessory molecule-1, (TIGIT) T-cell immunoreceptor with Ig and ITIM domains, (KLRG1) killer cell lectin-like receptor G1.

Figure 2.

Hepatitis C virus (HCV) patients have increased galectin-9 expression in Kupffer cells. Immunohistochemistry was used to stain for galectin-9 protein in paraffin-embedded liver biopsy samples from HCV-infected patients and normal control subjects. Kupffer cells can be identified by their characteristic cigar-shaped morphology. (A) Galectin-9 staining in normal liver (brown). (B) Galectin-9 staining in an HCV patient showing clear up-regulation (Mengshol et al. 2010).

Figure 3.

Natural killer (NK) cells contribute to control of hepatitis C virus (HCV) infection. NK cells have been implicated at every stage of HCV infection; the association of NK cells with natural history, acute and chronic infection, and treatment outcome is shown. (KIR) killer immunoglobulin-like receptor, (MHC I) major histocompatibility complex class I, (NCRs) natural cytotoxicity receptors, (TRAIL) TNF-related apoptosis-inducing ligand, (IFN-γ) interferon γ, (NKG2) natural killer group 2 D/A, (SVR) sustained virological response.