Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection

Abstract

Generalized CD8+ T-cell impairment in chronic hepatitis C virus (HCV) infection and the contribution of liver-infiltrating CD8+ T-cells to the immunopathogenesis of this infection remain poorly understood. It is hypothesized that this impairment is partially due to reduced CD8+ T-cell activity in response to cytokines such as IL-7, particularly within the liver. To investigate this, the phenotype and cytokine responsiveness of blood- and liver-derived CD8+ T-cells from healthy controls and individuals with HCV infection were compared. In blood, IL-7 receptor α (CD127) expression on bulk CD8+ T-cells in HCV infection was no different than controls yet was lower on central memory T-cells, and there were fewer naïve cells. IL-7-induced signalling through phosphorylated STAT5 was lower in HCV infection than in controls, and differed between CD8+ T-cell subsets. Production of Bcl-2 following IL-7 stimulation was also lower in HCV infection and inversely related to the degree of liver fibrosis. In liver-derived CD8+ T-cells, STAT5 activation could not be increased with cytokine stimulation and basal Bcl-2 levels of liver-derived CD8+ T-cells were lower than blood-derived counterparts in HCV infection. Therefore, generalized CD8+ T-cell impairment in HCV infection is characterized, in part, by impaired IL-7-mediated signalling and survival, independent of CD127 expression. This impairment is more pronounced in the liver and may be associated with an increased potential for apoptosis. This generalized CD8+ T-cell impairment represents an important immune dysfunction in chronic HCV infection that may alter patient health.

Hepatitis C virus core protein reduces CD8+ T‐cell proliferation, perforin production and degranulation but increases STAT5 activation

“…We also found that anti-apoptotic Bcl-2 up-regulation is inhibited by HCV core, suggesting that the viral protein may contribute to the reduced survival potential of CD8 + T-cells observed in chronic HCV infection. 10 Interleukin-7-mediated Bcl-2 production enhances the survival of naive CD8 + T-cells and the development of memory CD8 + T-cells. 24,25 Hence, HCV core, by reducing Bcl-2 up-regulation, may reduce the presence of viable CD8 + T-cells and impair the development of memory responses.…”

“…Expression of anti-apoptotic B-cell chronic lymphocytic leukaemia/lymphoma 2 (Bcl-2) protein and activation of its upstream regulator signal transducer and activator of transcription 5 (STAT5) has also been shown to be lower in bulk CD8 + T-cells in chronically infected HCV + individuals, indicating lower survival potential or viability. 10 Increased activation-induced apoptosis and unique pro-apoptotic gene signature in bulk T-cells in HCV infection has also been observed. 8 Generalized impairment of CD8 + T-cells may contribute to observed decreases in immunity to other viral infections and cancers during HCV infection.…”

“…20 We therefore sought to determine whether HCV core protein directly contributes to CD8 + T-cell impairment, as is observed in HCV infection. 10 We evaluated effects on CD8 + T-cell activity, survival potential and effector functions. Our study provides novel insights into HCV core protein-mediated impairment of bulk CD8 + T-cells, which in turn will contribute to the observed generalized CD8 + T-cell dysfunction in chronic HCV infection.…”

“…showed that in HCV‐infected patients, cytomegalovirus‐specific CD8 + T‐cells produced less Fas ligand and perforin, and lost markers of maturity but exhibited appropriate proliferative capacity. Expression of anti‐apoptotic B‐cell chronic lymphocytic leukaemia/lymphoma 2 (Bcl‐2) protein and activation of its upstream regulator signal transducer and activator of transcription 5 (STAT5) has also been shown to be lower in bulk CD8 + T‐cells in chronically infected HCV + individuals, indicating lower survival potential or viability . Increased activation‐induced apoptosis and unique pro‐apoptotic gene signature in bulk T‐cells in HCV infection has also been observed …”

“…We therefore sought to determine whether HCV core protein directly contributes to CD8 + T‐cell impairment, as is observed in HCV infection . We evaluated effects on CD8 + T‐cell activity, survival potential and effector functions.…”