Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections (original) (raw)
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Journal of Virology, 2008
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.
The Journal of Immunology, 2002
The cellular immune response contributes to clearance of hepatitis C virus (HCV) and persists for decades after recovery from infection. The immunological basis for the inefficiency of the cellular immune response in chronically infected persons is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, to investigate at the single-cell level effector function and phenotype of HCV-specific CD8 ؉ T cells in 20 chronically infected and 12 long-term recovered patients. Overall, HCV-specific, tetramer ؉ T cells were more frequently found in PBMCs of chronically infected patients than in those of recovered patients. However, when compared with HCV-tetramer ؉ T cells of recovered patients, they displayed an impaired proliferative capacity. As a result of the impaired proliferative capacity, HCV-specific T cell lines derived from chronically infected patients displayed less peptide-specific cytotoxicity than those from recovered patients. In addition, proliferation and ex vivo IFN-␥ production of HCV-tetramer ؉ cells, but not influenza-virus-specific T cells, were defective in chronically infected patients and could not be restored by in vitro stimulation with peptide and IL-2. At least three distinct phenotypes of HCV-specific CD8 ؉ T cells were identified and associated with certain functional characteristics. In addition, impairment of proliferative, cytokine, and cytotoxic effector functions of tetramer ؉ T cells in viremic patients was associated with weak ex vivo HCV-specific CD4 ؉ T cell responses. Thus, the defective functions of HCV-specific CD8 ؉ T cells might contribute to viral persistence in chronically infected patients, and knowledge on their reversibility may facilitate the development of immunotherapeutic vaccines.
European Journal of Immunology, 2004
In a companion study, we showed a dichotomy between the expansion of central memory (CCR7 + ) hepatitis C virus (HCV)-specific CTL and the incomplete memory effector differentiation in patients with acute HCV infection. Indeed, effector cells were unable to perform immediate functions, despite expressing the tissue-homing phenotype of effector memory cells (CCR7 -; semi-effectors). However, since they promptly differentiated into full-effectors upon IL-2 contact, we suggested that the inhibitory effect by environmental (possibly viral) factors on IL-2 production may have a pivotal role in generating the large population of semieffector CCR7 -/IFN-+ -CTL. In accord with this view, we report here strong evidence in support of circulating HCV core protein (HCVcore) playing a central role in inhibiting effector CTL differentiation, but not memory CTL expansion. The regulatory HCVcore effect is related to inhibition of the signal transduction pathway instrumental for IL-2 production, supporting the evidence that IL-2 was capable both of pushing semi-effector CTL to complete their effector cell program and of restoring the HCVcore-dependent inhibitory effect. Therefore, the strength of CTL activation is dependent on the balance between the threshold of stimulatory signals and the viral interference capacities provided during priming.
Expression of CD8? identifies a distinct subset of effector memory CD4 + T lymphocytes
Immunology, 2006
Circulating CD4 + CD8 + T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques. Two distinct populations of CD4 + CD8 + T cells were identified: the dominant one was CD4 hi CD8 lo and expressed the CD8aa homodimer, while the minor population was CD4 lo CD8 hi and expressed the CD8ab heterodimer. The majority of CD4 hi CD8a lo T cells exhibited an activated effector/memory phenotype (CCR5 lo CD7-CD28-HLA-DR +) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4 hi CD8a lo T cells compared to single-positive CD4 + T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4 hi CD8a lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4 hi CD8a lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4 + T cells expressing CD8a represent an effector/memory subset of CD4 + T cells and that this cell population can be depleted during the course of SIV infection.
Expression of CD8? identifies a distinct subset of effector memory CD4+T lymphocytes
Immunology, 2006
Circulating CD4 + CD8 + T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques. Two distinct populations of CD4 + CD8 + T cells were identified: the dominant one was CD4 hi CD8 lo and expressed the CD8aa homodimer, while the minor population was CD4 lo CD8 hi and expressed the CD8ab heterodimer. The majority of CD4 hi CD8a lo T cells exhibited an activated effector/memory phenotype (CCR5 lo CD7-CD28-HLA-DR +) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4 hi CD8a lo T cells compared to single-positive CD4 + T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4 hi CD8a lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4 hi CD8a lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4 + T cells expressing CD8a represent an effector/memory subset of CD4 + T cells and that this cell population can be depleted during the course of SIV infection.
European Journal of Immunology, 2000
Cellular immune responses are likely to play a key role in determining the clinical outcome in acute infection with hepatitis C virus (HCV), but the dynamics of such responses and their relationship to viral clearance are poorly understood. In a previous study we have shown highly activated, multispecific cytotoxic T lymphocyte responses arising early and persisting in an individual who subsequently cleared the virus. In this study the HCV-specific CD8 + lymphocytes response has been similarly analyzed, using peptide-HLA class I tetramers, in a further nine individuals with documented acute HCV infection, six of whom failed to clear the virus. Significant populations of virus-specific CD8 + lymphocytes were detected at the peak of acute hepatic illness (maximally 3.5 % of CD8 + lymphocytes). Frequencies were commonly lower than those seen previously and were generally not sustained. Early HCVspecific CD8 + lymphocytes showed an activated phenotype in all patients (CD38 + and HLA class II + ), but this activation was short-lived. Failure to sustain sufficient numbers of activated virus-specific CD8 + lymphocytes may contribute to persistence of HCV.
Sustained Dysfunction of Antiviral CD8+ T Lymphocytes after Infection with Hepatitis C Virus
Journal of Virology, 2001
Hepatitis C virus (HCV) sets up persistent infection in the majority of those exposed. It is likely that, as with other persistent viral infections, the efficacy of T-lymphocyte responses influences long-term outcome. However, little is known about the functional capacity of HCV-specific T-lymphocyte responses induced after acute infection. We investigated this by using major histocompatibility complex class I-peptide tetrameric complexes (tetramers), which allow direct detection of specific CD8 ؉ T lymphocytes ex vivo, independently of function. Here we show that, early after infection, virus-specific CD8 ؉ T lymphocytes detected with a panel of four such tetramers are abnormal in terms of their synthesis of antiviral cytokines and lytic activity. Furthermore, this phenotype is commonly maintained long term, since large sustained populations of HCV-specific CD8 ؉ T lymphocytes were identified, which consistently had very poor antiviral cytokine responses as measured in vitro. Overall, HCV-specific CD8 ؉ T lymphocytes show reduced synthesis of tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) after stimulation with either mitogens or peptides, compared to responses to Epstein-Barr virus and/or cytomegalovirus. This behavior of antiviral CD8 ؉ T lymphocytes induced after HCV infection may contribute to viral persistence through failure to effectively suppress viral replication.
Factors That Determine the Antiviral Efficacy of HCV-Specific CD8+ T Cells Ex Vivo
Gastroenterology, 2013
BACKGROUND & AIMS: Dysfunctional CD8 ϩ T cells are believed to contribute to the ability of hepatitis C virus (HCV) to evade the immune response. Most studies have focused on the effector functions of HCV-specific CD8 ϩ T cells or their surface expression of inhibitory receptors. There is currently no information available about the ex vivo ability of HCV-specific CD8 ϩ T cells to inhibit viral replication (antiviral efficacy). METHODS: To analyze the antiviral efficacy of virus-specific CD8 ϩ T cells ex vivo, we used an immunologic model based on a cell line that expresses HLA-A*02 and contains a stably replicating HCV reporter replicon. We isolated HCV-specific CD8 ϩ T cells from 18 HLA-A*02-positive patients with chronic HCV infection and 15 subjects with resolved HCV infection (7 spontaneous, 8 after therapy). Replicon cells were labeled with virus-specific peptides; inhibition of HCV replication was determined by measuring luciferase activity after 72 hours of coculture with virus-specific CD8 ϩ T cells. RESULTS: HCV-specific CD8 ϩ T cells from patients with chronic HCV infection had a significantly lower antiviral efficacy than influenza-, Epstein-Barr virus-, and cytomegalovirus-specific CD8 ϩ T cells. Antiviral efficacy was associated with the ability of virus-specific CD8 ϩ T cells to secrete interferon gamma. The antiviral efficacy of HCV-specific CD8 ϩ T cells was linked to surface expression of CD127 and PD-1. The cytokines interleukin-2, interleukin-7, and interleukin-15 increased the antiviral efficacy of CD127-positive but not of CD127-negative, HCV-specific CD8 ϩ T cells. Spontaneous, but not antiviral therapy-induced, viral clearance was associated with increased antiviral efficacy. CONCLUSIONS: The ability of CD8 ؉ T cells to inhibit HCV replication ex vivo is associated with their ability to secrete interferon gamma and their surface expression of CD127 and PD-1.