Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C

Abstract

Dysfunctional hepatitis C virus (HCV) specific CD4 + T cells are known to contribute to inadequate adaptive immunity in chronic hepatitis C (CHC), although the underlying mechanisms remain largely undefined. In this study, OX40 ligand (OX40L) expression was investigated in 41 treatment-naïve CHC patients, 20 sustained virological responders and 36 healthy subjects. We observed that OX40L expression was significantly upregulated in peripheral monocytes in CHC patients compared with sustained virological responders and healthy subjects. OX40L upregulation correlated significantly with plasma viral load rather than serum alanine aminotransaminase levels. Furthermore, longitudinal analyses indicated that upregulated OX40L expression on monocytes is closely associated with rapid or early virological responses in patients receiving pegylated IFN-α/ ribavirin treatment. In vitro, HCV core antigen strongly stimulated monocyte expression of OX40L and blockade of TLR2 signaling significantly downregulated OX40L expression. More importantly, elevated OX40L expression was also shown to be closely associated with elevation of the HCV-specific CD4 + T-cell response and in vitro blockade of OX40L expressed on monocytes led to impaired CD4 + T-cell function. These findings, therefore, implicate OX40L expression can be used as a marker to evaluate antiviral treatment efficacy and extend the notion that enhancement of OX40L expression could be a good way for immunotherapy in CHC patients. Keywords: Chronic hepatitis C (HCV) r Monocyte r OX40 ligandAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Fu-Sheng Wang e-mail: fswang302@163.com * These authors contributed equally to this study. 1954 Ji-Yuan Zhang et al. Eur. J. Immunol. 2013. 43: 1953-1962 Introduction The hepatitis C virus (HCV) leads to chronic infection and viral persistence in 85% of infected individuals and an estimated 180 million people are infected worldwide [1,2]. In China, HCV has gradually become a major public health problem, with anti-HCV prevalence in the general population at approximately 3.2%. This level increases with age, thus implicating age as an individual risk factor for HCV infection [3]. Following exposure to HCV, CD4 + and CD8 + T-cell responses to HCV are stronger in patients exhibiting spontaneous resolution of HCV infection, whereas the decay of virus-specific T cells, manifested as functional impairment of proliferative and lytic capacity and exhausted cytokine production, is observed in patients developing chronicity of HCV infection. Furthermore, during acute self-limited HCV infections, HCV-specific CD4 + T cells have been shown to play a crucial role in the maintenance of an effective ongoing CD8 + T-cell response. In contrast, the impaired capacity of HCV-specific CD4 + T cells is thought to be one of the key mechanisms responsible for the compromised protective CD8 + T-cell responses [4,5].Expression of OX40 ligand (OX40L), a TNF family member, has been...

Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue

“…In line with data by others, OX40L expression by mono/MF directly correlated with HCV viral load. Because some data suggest high viremia as a risk factor for HCC development or recurrence, and because Treg intratumoral accumulation is associated with unfavorable HCC prognosis, we are tempted to speculate that high HCV load may support tumor progression also through OX40L‐mediated local Treg expansion and the resulting immune suppression.…”

“…Rather, virus‐dependent factors may affect OX40L levels: Indeed, OX40L expression directly correlated with plasmatic viral load in all samples examined (Fig. E) . Suggesting OX40L as a signal playing peculiar functions in CHC, we found a trend toward a lower OX40L expression level in mono/MF from PB, NT‐LIV, or TUM tissues from a small cohort of pts with non‐CHC‐related cirrhosis, even if these differences lacked statistical significance (Supporting Tables 2 and 3; Fig.…”

An OX40/OX40L interaction directs successful immunity to hepatitis B virus

“…Furthermore, we also show that effective immunity to HBV, including IL-21 production by T FH , a strong and diverse primary T cell response, HBsAb seroconversion, and HBsAg clearance, is OX40/OX40L-dependent. The HBV age-dependent aspect aside, our data are consistent with studies demonstrating a role for OX40/OX40L interaction in the expansion and maintenance of T cell responses against other viruses (12–15, 21–24). …”

OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response

“…OX40L + myeloid APCs in pediatric tonsils were also largely limited to the CD14 + population. Increased OX40L expression on blood monocyte populations was also reported in patients with sepsis (Karulf et al, 2010) and patients with chronic hepatitis C (Zhang et al, 2013). Interestingly, both disease conditions are known to be often associated with hyper gammaglobulinemia.…”