PD-1 tempers Tregs in chronic HCV infection

Adaptive T cell responses are critical for controlling infections with viruses such as HIV, HBV, and HCV. However, these responses must be carefully regulated because overly vigorous T cell activation can lead to excessive host tissue damage. T cell expression of the inhibitory receptor programmed death–1 (PD-1) and inhibition of effector T cells (Teffs) by CD4+Foxp3+ Tregs are among the many described mechanisms for achieving a balanced immune response. Although the signals that contribute to Teff function are well understood, less is known about the signals controlling Tregs. In this issue of the JCI, Franceschini et al. extend our understanding of how Tregs are modulated during chronic HCV infection by demonstrating that Treg proliferation is inhibited by PD-1 and that this inhibition is mediated by a potentially novel mechanism involving the prevention of IL-2–driven STAT-5 phosphorylation (see the related article beginning on page 551)

Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection▿

A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections

Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression

The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8(+) antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8(+) T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8(+) T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication