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.

The immunodeficiency that follows HIV infection is related to the virus-mediated killing of infected CD4+ T cells, the chronic activation of the immune system, and the impairment of T cell production. In this study we show that in HIV-infected individuals the loss of IL-7R (CD127) expression defines the expansion of a subset of CD8+ T cells, specific for HIV as well as other Ags, that show phenotypic (i.e., loss of CCR7 and CD62 ligand expression with enrichment in activated and/or proliferating cells) as well as functional (i.e., production of IFN-γ, but not IL-2, decreased ex vivo proliferative potential and increased susceptibility to apoptosis) features of effector T cells. Importantly, in HIV-infected individuals the levels of CD8+CD127− T cells are directly correlated with the main markers of disease progression (i.e., plasma viremia and CD4+ T cell depletion) as well as with the indices of overall T cell activation. In all, these results identify the expansion of CD8+CD127− effector-like T cells as a novel feature of the HIV-associated immune perturbation. Further studies are thus warranted to determine whether measurements of CD127 expression on CD8+ T cells may be useful in the clinical management of HIV-infected individuals.

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 HCVspecific 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 HCVspecific 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.Hepatitis C virus (HCV) infects more than 150 million people worldwide (3, 61) and is a major cause of liver failure in the United States (41). Current treatments for chronic HCV infection cure only approximately 50% of persons infected with genotype 1 virus, the most prevalent genotype in the United States (49). In addition to limitations in efficacy, current antiviral therapy is prolonged and associated with disabling side effects, highlighting the need for improved therapeutic options.The adaptive T-cell immune response is important in mediating HCV clearance (10,14,19,36,42,55), yet the reason that a majority of infected patients develop only a weak, narrow, or nonpersistent adaptive response to acute infection is not well understood. Studies of some patients acutely infected with HCV show impairment of cytokine production and proliferation of HCV-specific CD8 ϩ T cells during the acute phase even though antigen-specific cells are present at a high frequency during this phase of infection (55). A period of "stunning" of HCV-specific CD8 ϩ T cells during the earliest time points has been observed (36). During the chronic phase of HCV infection, HCV-specific CD8 ϩ T cells also display significant functional deficits including impaired cytokine production and proliferative capacity (21, 62). Programmed death receptor 1 (PD-1) is an inhibitory receptor in the CD28 family that is expressed on antigen-specific T cells during acute and chronic viral infections (reviewed...

Summary The hallmark of effective establishment of immune memory is the long‐term memory cell that persists in the absence of antigen. To explore its characteristics, we investigated the differences between a resolved successful immune response, such as after influenza (flu) vaccination, and the state of chronic infection with persistent antigen, such as with cytomegalovirus (CMV), Epstein–Barr virus (EBV) or human immunodeficiency virus (HIV), which leads to defective T‐cell memory. Immunophenotypic analyses using multi‐parameter flow cytometry and tetramer technology identified a unique pattern of CD26high expression among influenza‐specific CD8+ T cells, but not among CD8+ T cells specific for CMV, EBV (three different epitopes) or HIV. The median percentage of CD8+ T cells expressing CD26 was 95·5% for influenza, but for cells specific for CMV, EBV and HIV it was 10·5%, 12%–19%, and 13·2%, respectively. These findings suggest that expression of CD26high may be a characteristic of a memory cell. CD26high expression correlates with expression of CD127, a marker of memory cells. Furthermore, CD26high cells can produce interleukin‐2. These findings offer insight into the dynamics of T‐cell differentiation, and they may offer a specific marker of a successfully developed memory CD8+ T cell, that of CD26high. This marker has the potential to be useful in studies of immune responses to infectious agents, and to new vaccine candidates.