HCV-Specific Interleukin-21+CD4+ T Cells Responses Associated with Viral Control through the Modulation of HCV-Specific CD8+ T Cells Function in Chronic Hepatitis C Patients

Abstract

Interleukin-21 (IL-21)+CD4+ T cells are involved in the immune response against hepatitis B virus (HBV) by secreting IL-21. However, the role of IL-21+CD4+ T cells in the immune response against chronic hepatitis C (CHC) virus infection is poorly understood. This study aimed to investigate the role of IL-21+CD4+ T cells in CHC patients and the potential mechanisms. The study subjects included nineteen CHC patients who were grouped by viral load (low, < 10 6 RNA copies/ml, n = 8; high, > 10 6 RNA copies/ml, n = 11). The peripheral frequency of HCV-specific IL-21+CD4+ T cells was higher in the low viral load group and was negatively correlated with the serum HCV RNA viral load in all CHC patients. Meanwhile, IL-21+ cells accumulated in the liver in the low viral load group. In vitro, IL-21 treatment increased the expression of proliferation markers and cytolytic molecules on HCV-specific CD8+ T cells. In summary, these findings suggest that HCV-specific IL-21+CD4+ T cells might contribute to HCV control by rescuing HCV-specific CD8+ T cells in CHC patients.

T cell exhaustion during persistent viral infections

“…The importance of IL-21 in maintaining anti-viral CD8 T cell responses has also been reported during HIV infections where the fraction of IL-21 producing T cells correlates with superior anti-viral CD8 T cell responses and viral control (Chevalier et al, 2011; Iannello et al, 2010; Williams et al, 2011; Yue et al, 2010). Moreover, higher levels of IL-21 are also associated with better containment of HBV and HCV infections (Feng et al, 2013; Kared et al, 2013; Spaan et al, 2014). …”

The proportion of different interleukin‐17‐producing T‐cell subsets is associated with liver fibrosis in chronic hepatitis C

“…In the early stages of the disease, for example, the production of IL‐21 by Th17 cells has been convincingly linked to protection and spontaneous healing after the acute phase of HCV infection . In our CHC patients, the proportion of this cell subset could also be related to better liver disease outcomes, as its percentage was higher among patients with lower hepatic lesions and plasmatic ALT levels.…”

“…Further, the proportion of single IFN‐ γ ‐producing CD4 + and CD8 + T lymphocytes, which include Th1 and Tc‐1 cells, was lower among CHC patients with higher liver fibrosis scores (data not shown). Indeed, early IFN‐ γ production by HCV‐specific T cells is involved in protecting against HCV …”

“…20 Moreover, IL-21-producing Th17 cells during the acute phase have been convincingly linked to disease resolution and HCV clearance. 21 These authors observed a direct correlation between IL-21 levels and polyfunctional HCV-specific CD8 + T cells, identified by IFN-c production and lower PD-1 and Tim-3 expression. 16,21 Altogether, these results suggest that protective or deleterious involvement of IL-17-secreting T cells may depend on the cytokine arrays produced by these cells in response to HCV.…”

“…In the context of chronic hepatitis C (CHC), for example, dual IL‐17 and IFN‐ γ ‐producing CD8 + T cells were associated with a better prognosis for liver disease . Moreover, IL‐21‐producing Th17 cells during the acute phase have been convincingly linked to disease resolution and HCV clearance . These authors observed a direct correlation between IL‐21 levels and polyfunctional HCV‐specific CD8 + T cells, identified by IFN‐ γ production and lower PD‐1 and Tim‐3 expression .…”