A View to Natural Killer Cells in Hepatitis C
Centre de Recherche du Centre Hospitalier de l'Université de Montréal and, Département de médecine, Université de Montréal. Gastroenterology
(Impact Factor: 16.72).
08/2011; 141(4):1144-8. DOI: 10.1053/j.gastro.2011.08.025
Available from: sciencedirect.com
- ". A possible role of NK cells in HCV immunobiology is further supported by the finding that they are activated in acutely infected subjects, as determined by an increased expression of the activating receptor NKG2D that is accompanied by an increased production of IFN-c and cytotoxicity . NK cell responses are also linked with T cell responses, e.g., increased degranulation of natural killer cells during acute HCV has been shown to correlate with the magnitude of virus-specific T cell responses  . Also, an activated multifunctional NK cell response, i.e., cytotoxicity and IFN-c production, has been reported early after HCV exposure in healthcare workers who do not develop acute infection, suggesting an important contribution to the prevention of high level viremia  . "
[Show abstract] [Hide abstract]
ABSTRACT: Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection.
- "Type I IFN activated NK cells were found to induce apoptosis of HCV-infected hepatoma cells through a TRAIL-triggered cell death pathway [3,4,6,8–10]. However, it is still unclear whether another important aspect of NK cells, IFN-c production, is induced and whether NK cell-derived cytokines play any roles in response to hepatitis C infection . Here using co-cultures of human immune cells and JFH-1 infected hepatoma cells, we revealed a novel mechanism in which NK cells produced IFN-c in response to HCV-infected cells through a pDC-type I IFN dependent mechanism. "
[Show abstract] [Hide abstract]
ABSTRACT: Background & aims:
Interferon-γ (IFN-γ), 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-γ 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-γ 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-γ producers within PBMCs. Purified NK/NKT cells did not produce IFN-γ in response to JFH-1/HuH7.5 cells and depletion of accessory (HLA-DR(+)) cells prevented IFN-γ 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-γ induction and the presence of monocytes was needed for maximal NK-IFN-γ induction. We further revealed that NK-IFN-γ induction depended on pDC-derived IFN-α while other IFN-γ 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-γ production and monocyte-derived IL-15 significantly augmented IFN-γ induction.
We discovered a novel mechanism where NK cells interact with pDCs and monocytes, efficiently producing IFN-γ in response to HCV-infected cells. This indicates that co-operation between NK cells and accessory cells is critical for IFN-γ production and regulation of immunity during HCV infection.
Available from: Andres Duarte-Rojo
[Show abstract] [Hide abstract]
ABSTRACT: The discovery of the IL28B single-nucleotide polymorphisms (SNPs) has opened an important new area of research in liver transplantation (LT) for hepatitis C (HCV). Both recipient and donor derived IL28B genotypes affect post-LT treatment response, with sustained virological response (SVR) rates oscillating between >50% in homozygotes for the favorable allele (up to 90% when this is present in both recipient and donor), to <15% SVR in homozygotes for the unfavorable allele, and 30-50% in the heterozygotes. Other key posttransplant outcomes affected by IL28B genotype are time to histological recurrence, HCV RNA and ALT levels, histological variables including the rate of fibrosis progression, and hepatocarcinoma. Interactions between donor and recipient IL28B genotype are complex and may affect outcomes not directly related to HCV infection, such as acute cellular rejection and metabolic diseases. A preferential allocation system, in which livers from donors who are homozygous for the favorable allele are given to HCV patients, might be postulated to improve SVR and post-LT outcomes in recipients with HCV infection (25% increase in SVR and 8% decrease in mortality at 5 years). Although difficult to predict, negative effects from this could include an accelerated progression of fibrosis in patients with failed HCV eradication, and an increase in acute cellular rejection in non-HCV patients. The precise role of IL28B genotypes in the course of post-LT HCV is evolving, but existing knowledge suggests the possibility of exploring strategies that use IL28B genotyping to reduce the impact of post-LT adverse outcomes. Liver Transpl, 2012. © 2012 AASLD.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.