Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus - PubMed (original) (raw)

Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus

N H Gruener et al. J Virol. 2001 Jun.

Abstract

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-alpha) and gamma interferon (IFN-gamma) 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.

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Figures

FIG. 1

Dynamics of hepatitis and acute immune responses in two subjects. (a) Time course of disease and immune responses. (Upper panels) Time course of alanine aminotransferase (ALT [international units per milliliter]) in serum over time. Subject A was PCR positive (+) for HCV RNA at the first time point and subsequently became PCR negative (−) over time as indicated, with recrudescence at week 15. In subject B, virus did not recrudesce, even during longer follow-up periods of 1 year. (Middle panels) Dynamics of tetramer-positive responses. Frozen PBMCs were thawed and tested in parallel with tetramers for four HLA-A2-restricted peptides (NS3 1073, NS3 1406, NS4B 1807, and NS5B 2594). Thawed PBMCs were stained exactly as previously described (19, 21). Only positive stains are shown. The proportions were calculated after gating on live CD8+ lymphocytes. (Lower panels) Fresh PBMCs were tested in standard proliferation assays by incorporation of [3H]thymidine after stimulation with HCV antigens as previously described (11). (b) Phenotype of acute responses in subject A. Frozen PBMCs were thawed and stained in parallel with the tetramers for NS3 1073 and NS5 2094, shown to be positive, together with the antibodies for MHC class II CD38, CCR-5, or (after permeabilization) Ki-67 (see Materials and Methods). The proportions of tetramer-positive cells staining positive at each time point for each marker are shown. (c) PMA-ionomycin-stimulated cytokine synthesis over time in subject B. Frozen PBMCs were thawed, tetramer stained for 20 min, and then stimulated with PMA-ionomycin as previously described (21). Staining with PerCP-labeled anti-CD8 was followed by permeabilization as in panel b and intracellular staining with FITC–anti-IFN-γ (Becton Dickinson). After four-color flow cytometry, the proportion of tetramer-positive cells staining positive for intracellular IFN-γ was calculated. (d) Peptide-stimulated synthesis of IFN-γ in subject B: comparison of HCV and control response. Frozen PBMCs from subject B at weeks 2 and 14 were thawed, stained with tetramers for HCV NS3 1073 or CMV, stimulated with the appropriate peptide and costimulatory molecules, permeabilized, and stained for CD8 and intracellular IFN-γ (21). After flow cytometric analysis, the CD8+ population is displayed. The proportion of tetramer-positive cells staining positive for IFN-γ is shown. Staining of cells in the absence of peptide revealed stimulation of <2% in both cases. (e) Peptide-stimulated upregulation of CD69 in subject B: comparison of HCV and control responses. PBMCs from the same time points as in panel d above were stimulated in the same manner with peptide (21) and stained thereafter with PerCP–anti-CD8 and FITC–anti-CD69. The proportion of tetramer-positive cells expressing CD69 is illustrated. Expression in ex vivo samples or in the absence of peptide was <2%. (f) Example of CD69 upregulation in tetramer-positive populations by peptide stimulation. Examples from the first time point of CD69 surface staining in tetramer-positive cells. The tetramer-positive CD8+ population was gated upon and CD69 expression was analyzed after peptide stimulation. No upregulation of CD69 on tetramer-negative cells was observed (data not shown).

FIG. 1

Dynamics of hepatitis and acute immune responses in two subjects. (a) Time course of disease and immune responses. (Upper panels) Time course of alanine aminotransferase (ALT [international units per milliliter]) in serum over time. Subject A was PCR positive (+) for HCV RNA at the first time point and subsequently became PCR negative (−) over time as indicated, with recrudescence at week 15. In subject B, virus did not recrudesce, even during longer follow-up periods of 1 year. (Middle panels) Dynamics of tetramer-positive responses. Frozen PBMCs were thawed and tested in parallel with tetramers for four HLA-A2-restricted peptides (NS3 1073, NS3 1406, NS4B 1807, and NS5B 2594). Thawed PBMCs were stained exactly as previously described (19, 21). Only positive stains are shown. The proportions were calculated after gating on live CD8+ lymphocytes. (Lower panels) Fresh PBMCs were tested in standard proliferation assays by incorporation of [3H]thymidine after stimulation with HCV antigens as previously described (11). (b) Phenotype of acute responses in subject A. Frozen PBMCs were thawed and stained in parallel with the tetramers for NS3 1073 and NS5 2094, shown to be positive, together with the antibodies for MHC class II CD38, CCR-5, or (after permeabilization) Ki-67 (see Materials and Methods). The proportions of tetramer-positive cells staining positive at each time point for each marker are shown. (c) PMA-ionomycin-stimulated cytokine synthesis over time in subject B. Frozen PBMCs were thawed, tetramer stained for 20 min, and then stimulated with PMA-ionomycin as previously described (21). Staining with PerCP-labeled anti-CD8 was followed by permeabilization as in panel b and intracellular staining with FITC–anti-IFN-γ (Becton Dickinson). After four-color flow cytometry, the proportion of tetramer-positive cells staining positive for intracellular IFN-γ was calculated. (d) Peptide-stimulated synthesis of IFN-γ in subject B: comparison of HCV and control response. Frozen PBMCs from subject B at weeks 2 and 14 were thawed, stained with tetramers for HCV NS3 1073 or CMV, stimulated with the appropriate peptide and costimulatory molecules, permeabilized, and stained for CD8 and intracellular IFN-γ (21). After flow cytometric analysis, the CD8+ population is displayed. The proportion of tetramer-positive cells staining positive for IFN-γ is shown. Staining of cells in the absence of peptide revealed stimulation of <2% in both cases. (e) Peptide-stimulated upregulation of CD69 in subject B: comparison of HCV and control responses. PBMCs from the same time points as in panel d above were stimulated in the same manner with peptide (21) and stained thereafter with PerCP–anti-CD8 and FITC–anti-CD69. The proportion of tetramer-positive cells expressing CD69 is illustrated. Expression in ex vivo samples or in the absence of peptide was <2%. (f) Example of CD69 upregulation in tetramer-positive populations by peptide stimulation. Examples from the first time point of CD69 surface staining in tetramer-positive cells. The tetramer-positive CD8+ population was gated upon and CD69 expression was analyzed after peptide stimulation. No upregulation of CD69 on tetramer-negative cells was observed (data not shown).

FIG. 1

Dynamics of hepatitis and acute immune responses in two subjects. (a) Time course of disease and immune responses. (Upper panels) Time course of alanine aminotransferase (ALT [international units per milliliter]) in serum over time. Subject A was PCR positive (+) for HCV RNA at the first time point and subsequently became PCR negative (−) over time as indicated, with recrudescence at week 15. In subject B, virus did not recrudesce, even during longer follow-up periods of 1 year. (Middle panels) Dynamics of tetramer-positive responses. Frozen PBMCs were thawed and tested in parallel with tetramers for four HLA-A2-restricted peptides (NS3 1073, NS3 1406, NS4B 1807, and NS5B 2594). Thawed PBMCs were stained exactly as previously described (19, 21). Only positive stains are shown. The proportions were calculated after gating on live CD8+ lymphocytes. (Lower panels) Fresh PBMCs were tested in standard proliferation assays by incorporation of [3H]thymidine after stimulation with HCV antigens as previously described (11). (b) Phenotype of acute responses in subject A. Frozen PBMCs were thawed and stained in parallel with the tetramers for NS3 1073 and NS5 2094, shown to be positive, together with the antibodies for MHC class II CD38, CCR-5, or (after permeabilization) Ki-67 (see Materials and Methods). The proportions of tetramer-positive cells staining positive at each time point for each marker are shown. (c) PMA-ionomycin-stimulated cytokine synthesis over time in subject B. Frozen PBMCs were thawed, tetramer stained for 20 min, and then stimulated with PMA-ionomycin as previously described (21). Staining with PerCP-labeled anti-CD8 was followed by permeabilization as in panel b and intracellular staining with FITC–anti-IFN-γ (Becton Dickinson). After four-color flow cytometry, the proportion of tetramer-positive cells staining positive for intracellular IFN-γ was calculated. (d) Peptide-stimulated synthesis of IFN-γ in subject B: comparison of HCV and control response. Frozen PBMCs from subject B at weeks 2 and 14 were thawed, stained with tetramers for HCV NS3 1073 or CMV, stimulated with the appropriate peptide and costimulatory molecules, permeabilized, and stained for CD8 and intracellular IFN-γ (21). After flow cytometric analysis, the CD8+ population is displayed. The proportion of tetramer-positive cells staining positive for IFN-γ is shown. Staining of cells in the absence of peptide revealed stimulation of <2% in both cases. (e) Peptide-stimulated upregulation of CD69 in subject B: comparison of HCV and control responses. PBMCs from the same time points as in panel d above were stimulated in the same manner with peptide (21) and stained thereafter with PerCP–anti-CD8 and FITC–anti-CD69. The proportion of tetramer-positive cells expressing CD69 is illustrated. Expression in ex vivo samples or in the absence of peptide was <2%. (f) Example of CD69 upregulation in tetramer-positive populations by peptide stimulation. Examples from the first time point of CD69 surface staining in tetramer-positive cells. The tetramer-positive CD8+ population was gated upon and CD69 expression was analyzed after peptide stimulation. No upregulation of CD69 on tetramer-negative cells was observed (data not shown).

FIG. 1

Dynamics of hepatitis and acute immune responses in two subjects. (a) Time course of disease and immune responses. (Upper panels) Time course of alanine aminotransferase (ALT [international units per milliliter]) in serum over time. Subject A was PCR positive (+) for HCV RNA at the first time point and subsequently became PCR negative (−) over time as indicated, with recrudescence at week 15. In subject B, virus did not recrudesce, even during longer follow-up periods of 1 year. (Middle panels) Dynamics of tetramer-positive responses. Frozen PBMCs were thawed and tested in parallel with tetramers for four HLA-A2-restricted peptides (NS3 1073, NS3 1406, NS4B 1807, and NS5B 2594). Thawed PBMCs were stained exactly as previously described (19, 21). Only positive stains are shown. The proportions were calculated after gating on live CD8+ lymphocytes. (Lower panels) Fresh PBMCs were tested in standard proliferation assays by incorporation of [3H]thymidine after stimulation with HCV antigens as previously described (11). (b) Phenotype of acute responses in subject A. Frozen PBMCs were thawed and stained in parallel with the tetramers for NS3 1073 and NS5 2094, shown to be positive, together with the antibodies for MHC class II CD38, CCR-5, or (after permeabilization) Ki-67 (see Materials and Methods). The proportions of tetramer-positive cells staining positive at each time point for each marker are shown. (c) PMA-ionomycin-stimulated cytokine synthesis over time in subject B. Frozen PBMCs were thawed, tetramer stained for 20 min, and then stimulated with PMA-ionomycin as previously described (21). Staining with PerCP-labeled anti-CD8 was followed by permeabilization as in panel b and intracellular staining with FITC–anti-IFN-γ (Becton Dickinson). After four-color flow cytometry, the proportion of tetramer-positive cells staining positive for intracellular IFN-γ was calculated. (d) Peptide-stimulated synthesis of IFN-γ in subject B: comparison of HCV and control response. Frozen PBMCs from subject B at weeks 2 and 14 were thawed, stained with tetramers for HCV NS3 1073 or CMV, stimulated with the appropriate peptide and costimulatory molecules, permeabilized, and stained for CD8 and intracellular IFN-γ (21). After flow cytometric analysis, the CD8+ population is displayed. The proportion of tetramer-positive cells staining positive for IFN-γ is shown. Staining of cells in the absence of peptide revealed stimulation of <2% in both cases. (e) Peptide-stimulated upregulation of CD69 in subject B: comparison of HCV and control responses. PBMCs from the same time points as in panel d above were stimulated in the same manner with peptide (21) and stained thereafter with PerCP–anti-CD8 and FITC–anti-CD69. The proportion of tetramer-positive cells expressing CD69 is illustrated. Expression in ex vivo samples or in the absence of peptide was <2%. (f) Example of CD69 upregulation in tetramer-positive populations by peptide stimulation. Examples from the first time point of CD69 surface staining in tetramer-positive cells. The tetramer-positive CD8+ population was gated upon and CD69 expression was analyzed after peptide stimulation. No upregulation of CD69 on tetramer-negative cells was observed (data not shown).

FIG. 1

Dynamics of hepatitis and acute immune responses in two subjects. (a) Time course of disease and immune responses. (Upper panels) Time course of alanine aminotransferase (ALT [international units per milliliter]) in serum over time. Subject A was PCR positive (+) for HCV RNA at the first time point and subsequently became PCR negative (−) over time as indicated, with recrudescence at week 15. In subject B, virus did not recrudesce, even during longer follow-up periods of 1 year. (Middle panels) Dynamics of tetramer-positive responses. Frozen PBMCs were thawed and tested in parallel with tetramers for four HLA-A2-restricted peptides (NS3 1073, NS3 1406, NS4B 1807, and NS5B 2594). Thawed PBMCs were stained exactly as previously described (19, 21). Only positive stains are shown. The proportions were calculated after gating on live CD8+ lymphocytes. (Lower panels) Fresh PBMCs were tested in standard proliferation assays by incorporation of [3H]thymidine after stimulation with HCV antigens as previously described (11). (b) Phenotype of acute responses in subject A. Frozen PBMCs were thawed and stained in parallel with the tetramers for NS3 1073 and NS5 2094, shown to be positive, together with the antibodies for MHC class II CD38, CCR-5, or (after permeabilization) Ki-67 (see Materials and Methods). The proportions of tetramer-positive cells staining positive at each time point for each marker are shown. (c) PMA-ionomycin-stimulated cytokine synthesis over time in subject B. Frozen PBMCs were thawed, tetramer stained for 20 min, and then stimulated with PMA-ionomycin as previously described (21). Staining with PerCP-labeled anti-CD8 was followed by permeabilization as in panel b and intracellular staining with FITC–anti-IFN-γ (Becton Dickinson). After four-color flow cytometry, the proportion of tetramer-positive cells staining positive for intracellular IFN-γ was calculated. (d) Peptide-stimulated synthesis of IFN-γ in subject B: comparison of HCV and control response. Frozen PBMCs from subject B at weeks 2 and 14 were thawed, stained with tetramers for HCV NS3 1073 or CMV, stimulated with the appropriate peptide and costimulatory molecules, permeabilized, and stained for CD8 and intracellular IFN-γ (21). After flow cytometric analysis, the CD8+ population is displayed. The proportion of tetramer-positive cells staining positive for IFN-γ is shown. Staining of cells in the absence of peptide revealed stimulation of <2% in both cases. (e) Peptide-stimulated upregulation of CD69 in subject B: comparison of HCV and control responses. PBMCs from the same time points as in panel d above were stimulated in the same manner with peptide (21) and stained thereafter with PerCP–anti-CD8 and FITC–anti-CD69. The proportion of tetramer-positive cells expressing CD69 is illustrated. Expression in ex vivo samples or in the absence of peptide was <2%. (f) Example of CD69 upregulation in tetramer-positive populations by peptide stimulation. Examples from the first time point of CD69 surface staining in tetramer-positive cells. The tetramer-positive CD8+ population was gated upon and CD69 expression was analyzed after peptide stimulation. No upregulation of CD69 on tetramer-negative cells was observed (data not shown).

FIG. 1

Dynamics of hepatitis and acute immune responses in two subjects. (a) Time course of disease and immune responses. (Upper panels) Time course of alanine aminotransferase (ALT [international units per milliliter]) in serum over time. Subject A was PCR positive (+) for HCV RNA at the first time point and subsequently became PCR negative (−) over time as indicated, with recrudescence at week 15. In subject B, virus did not recrudesce, even during longer follow-up periods of 1 year. (Middle panels) Dynamics of tetramer-positive responses. Frozen PBMCs were thawed and tested in parallel with tetramers for four HLA-A2-restricted peptides (NS3 1073, NS3 1406, NS4B 1807, and NS5B 2594). Thawed PBMCs were stained exactly as previously described (19, 21). Only positive stains are shown. The proportions were calculated after gating on live CD8+ lymphocytes. (Lower panels) Fresh PBMCs were tested in standard proliferation assays by incorporation of [3H]thymidine after stimulation with HCV antigens as previously described (11). (b) Phenotype of acute responses in subject A. Frozen PBMCs were thawed and stained in parallel with the tetramers for NS3 1073 and NS5 2094, shown to be positive, together with the antibodies for MHC class II CD38, CCR-5, or (after permeabilization) Ki-67 (see Materials and Methods). The proportions of tetramer-positive cells staining positive at each time point for each marker are shown. (c) PMA-ionomycin-stimulated cytokine synthesis over time in subject B. Frozen PBMCs were thawed, tetramer stained for 20 min, and then stimulated with PMA-ionomycin as previously described (21). Staining with PerCP-labeled anti-CD8 was followed by permeabilization as in panel b and intracellular staining with FITC–anti-IFN-γ (Becton Dickinson). After four-color flow cytometry, the proportion of tetramer-positive cells staining positive for intracellular IFN-γ was calculated. (d) Peptide-stimulated synthesis of IFN-γ in subject B: comparison of HCV and control response. Frozen PBMCs from subject B at weeks 2 and 14 were thawed, stained with tetramers for HCV NS3 1073 or CMV, stimulated with the appropriate peptide and costimulatory molecules, permeabilized, and stained for CD8 and intracellular IFN-γ (21). After flow cytometric analysis, the CD8+ population is displayed. The proportion of tetramer-positive cells staining positive for IFN-γ is shown. Staining of cells in the absence of peptide revealed stimulation of <2% in both cases. (e) Peptide-stimulated upregulation of CD69 in subject B: comparison of HCV and control responses. PBMCs from the same time points as in panel d above were stimulated in the same manner with peptide (21) and stained thereafter with PerCP–anti-CD8 and FITC–anti-CD69. The proportion of tetramer-positive cells expressing CD69 is illustrated. Expression in ex vivo samples or in the absence of peptide was <2%. (f) Example of CD69 upregulation in tetramer-positive populations by peptide stimulation. Examples from the first time point of CD69 surface staining in tetramer-positive cells. The tetramer-positive CD8+ population was gated upon and CD69 expression was analyzed after peptide stimulation. No upregulation of CD69 on tetramer-negative cells was observed (data not shown).

FIG. 2

Functional analysis of HCV-specific responses against three separate epitopes in three separate donors. (a) Cytokine release from CD8+ lymphocytes of different specificities. Frozen samples from three separate HCV antibody-positive individuals were thawed and tested for synthesis of antiviral cytokines after PMA-ionomycin stimulation exactly as in Fig. 1c. Both stains for TNF-α (right panels [marked FL4-H]) and IFN-γ (left panels [ifngFITC]) are illustrated. The numbers shown in each plot represent the percentage of tetramer-positive cells that stained positive for the particular cytokine. PCR-ve, PCR negative. (b) Control unstimulated cells and a reference for gating on the CD8 high population. Samples obtained from subject C (NS3 1073 specific) are illustrated. No synthesis of IFN-γ is seen. (c) Comparison of PMA-ionomycin and peptide stimulation. A CMV-specific response from a control HCV-negative patient is shown. The samples were tested in parallel for TNF-α synthesis according to the peptide stimulation and PMA stimulation protocols, and the CD8 high population is shown. Approximately similar proportions of CD8+ cytokine-positive cells were obtained, as indicated in the right upper quadrant of each FACS plot. (d) Analysis of Vβ usage of tetramer-positive cells in subjects A and B. PBMCs were anti-CD8 and tetramer stained as described above and costained with a panel of FITC-conjugated Vβ-specific MAbs (Immunotech, Marseille, France). Staining for Vβ3 only is shown, after gating on live CD8+ lymphocytes. A large population of Vβ3-positive, tetramer-positive lymphocytes is seen in subject B (30% of tetramer-positive cells), and a smaller population is seen in subject A (5%). No dominant Vβ usage was seen in subject A, C, or D. Tetramer-negative populations in these subjects did not reveal a major oligoclonal expansion when this restricted panel of antibodies was used (Vβ1, -2, -3, -5.1, -5.2, -5.3, -8, -9, -12, -13.1, -14, -16, -17, -20, -22, and -23).

FIG. 3

Functional analysis of a long-term antiviral CD8+ T-lymphocyte response. (a) Peptide-stimulated synthesis of cytokines in subject E: comparison of HCV and control responses. Experiments were performed exactly as in Fig. 1c. The CD8+ population is shown, and the proportions within the tetramer-positive populations that stain positive for intracellular cytokine are indicated. The upper panels represent stimulation with HCV peptide NS3 1073 (also indicated as “peptide 11” in the FACS plot title line), and the middle and lower panels represent HLA-A2-restricted peptides from CMV and EBV, respectively. (b) PMA-ionomycin-stimulated TNF-α synthesis in patient E. Experiments were performed exactly as in Fig. 2a. The CD8+ population is shown, and the proportions within the tetramer-positive and tetramer-negative populations positive for intracellular cytokine are indicated.

FIG. 4

Overall comparisons of HCV function and control responses. (Upper panel) Internal comparison. Five HCV antibody-positive subjects (all HCV PCR negative) for whom HCV and control responses were available were tested simultaneously for IFN-γ staining after PMA-ionomycin stimulation, and the proportion of tetramer-positive cells was calculated as in Fig. 2a, upper panels. Each HCV response was compared with the EBV and/or CMV response in the same individual (a total of eight comparisons). (Lower panel) Group comparison. Cytokine synthesis from HCV tetramer-positive populations in seven HCV antibody-positive subjects (five PCR negative) were tested exactly as described above (left-hand group, marked HCV) and compared with EBV and/or CMV responses within themselves and in seven normal controls (right-hand group). CMV and EBV responses from HCV antibody-positive subjects are shown by solid circles, and those from control subjects are shown by open circles.

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