Differential regulation of SOCS‐1 signalling in B and T lymphocytes by hepatitis C virus core protein

Abstract

SummaryHepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity, autoimmune phenomena and lymphomagenesis, supporting a role for lymphocyte dysregulation during persistent viral infection. We have shown that HCV core protein inhibits T-cell functions through interaction with a complement receptor, gC1qR. Here, we further report that B cells also express gC1qR that can be bound by HCV core protein. Importantly, using flow cytometry, we demonstrated differential regulation of B and T lymphocytes by the HCV core-gC1qR interaction, with down-regulation of CD69 activation in T cells but up-regulation of CD69 activation and cell proliferation in B cells. HCV core treatment led to decreased interferon-c production in CD8 + T cells but to increased immunoglobulin M and immunoglobulin G production as well as cell surface expression of costimulatory and chemokine receptors, including CD86 (B7-2), CD154 (CD40L) and CD195 (CCR5), in CD20 + B cells.Finally, we showed down-regulation of suppressor of cytokine signalling-1 (SOCS-1) using real-time reverse transcription-polymerase chain reaction, accompanied by up-regulation of signal transducer and activator of transcription-1 (STAT1) phosphorylation in B cells in response to HCV core protein, with the opposite pattern observed in HCV core-treated T cells. This study demonstrates differential regulation of B and T lymphocytes by HCV core and supports a mechanism by which lymphocyte dysregulation occurs in the course of persistent HCV infection.

Viral Exploitation of Host SOCS Protein Functions

“…Another associated disease, known as non-Hodgkin lymphoma, results directly from aberrant B cell proliferation (70). As previously mentioned, SOCS1 is decreased in B cells taken from HCV-infected patients (39) or those incubated with HCV core protein in vitro (74). Decreased SOCS1 expression correlates with increased STAT1 activation and with increases in both B cell proliferation and IgM/IgG production.…”

“…This is accompanied by decreases in STAT1 activation, markers of general T cell activation, and JAK/STAT-mediated IFN-␥ production, a response which greatly impedes the ability of CTLs to effectively clear viruses and promotes chronic HCV infection. In contrast, HCV core protein decreases the levels of SOCS1 in B cells (39,74). This decrease correlates with increased STAT1 activation and markers of general B cell activation, as well as increased B cell proliferation and antibody (IgM and IgG) production.…”

“…Stimulation of CD8 ϩ T cells with HCV core protein results in an increase in SOCS1 protein (74). This is accompanied by decreases in STAT1 activation, markers of general T cell activation, and JAK/STAT-mediated IFN-␥ production, a response which greatly impedes the ability of CTLs to effectively clear viruses and promotes chronic HCV infection.…”

Cross-Talk between Programmed Death-1 and Suppressor of Cytokine Signaling-1 in Inhibition of IL-12 Production by Monocytes/Macrophages in Hepatitis C Virus Infection

“…In addition to PD-1 dysregulation, we previously demonstrated that HCV core protein differentially regulated T and B lymphocyte functions by modulation of SOCS-1 (28)(29)(30)(31). To determine whether SOCS-1 is also involved in the negative regulation of M/M F IL-12 production during HCV infection, primary M/M F s were purified from healthy subjects and HCV-infected patients and stimulated with LPS/R848 for 24-48 h, followed by detection of SOCS-1 gene expression by RT-PCR and Western blotting.…”

“…One microgram of RNA was reverse transcribed using a GeneAmp RNA PCR kit (Applied Biosystems, Foster City, CA). SOCS-1 primers and RT-PCR conditions were described as reported previously (29). To control for genomic DNA contamination, equal amounts of cDNA from each sample were PCR amplified without reverse transcription.…”