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Preserved Function of Circulating Invariant Natural Killer T Cells in Patients With Chronic Hepatitis B Virus Infection.

ABSTRACT: To date, the role of invariant natural killer T (iNKT) cells in chronic hepatitis B virus (HBV) infection is not fully understood. In previous reports, iNKT cells were identified by indirect methods. However, discrepancies regarding the prevalence and function of iNKT cells during HBV infection were observed. In this study, we have devised a direct, highly specific CD1d tetramer-based methodology to test whether patients with HBV infection have associated iNKT-cell defects. In our study, a total of 93 chronic HBV-infected patients and 30 healthy individuals (as control) were enrolled. The prevalence of iNKT cells, their cytokine producing capacity, and in vitro expansion were determined by flow cytometric analysis with CD1d tetramer staining. Our observation demonstrated that there was no significant difference in circulating CD1d-tetramer positive iNKT cell numbers between HBV-infected patients and healthy controls. The capacity of iNKT cells to produce IFN-γ or IL-4 as well as their in vitro expansion was also comparable between these 2 groups. However, among chronic HBV-infected patients, a decrease in iNKT cell-number was observed in chronic hepatitis B (CHB) and cirrhosis patients in comparison to that in immune tolerant (IT) patients. These results indicated that patients with chronic HBV infection may have normal prevalence and preserved function of circulating iNKT cells. And antiviral therapy with nucleot(s)ide analogue does not alter the frequency and function of circulating iNKT cells in chronic Hepatitis B patients.

SUBMITTER: Zhu H

PROVIDER: S-EPMC4616535 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Project description:Background & aimsChronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer (NK) cells-the most prevalent innate immune cell in the liver. We investigated whether the elimination of hepatitis C virus with direct-acting antiviral normalizes expression of IFN-stimulated genes and NK cell function.MethodsWe used multicolor flow cytometry to analyze NK cells from the liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir and compared with samples from the blood of 13 healthy individuals (controls). Serum levels of chemokine C-X-C motif ligand (CXCL) 10 or CXCL11 were measured by enzyme-linked immunosorbent assay.ResultsBefore treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFNγ and tumor necrosis factor α compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (end of treatment).ConclusionsDirect-acting antiviral-mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, which is indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function.

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Preserved Function of Circulating Invariant Natural Killer T Cells in Patients With Chronic Hepatitis B Virus Infection.

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