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Journal of Virology, June 2001, p. 5550-5558, Vol. 75, No. 12
Institute for Immunology, D-80336
Munich,1 and Medical Department II,
Klinikum Grosshadern, D-81366 Munich,3 Germany;
Nuffield Department of Clinical Medicine, John Radcliffe
Hospital, Oxford OX3 9DU, United Kingdom2;
Infectious Diseases Unit and AIDS Research Center,
Massachussets General Hospital and Harvard Medical School, Boston,
Massachusetts 021294; and Australian Red
Cross Blood Service, Sydney 2000, Australia5
Received 23 January 2001/Accepted 12 March 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- Hepatitis C virus (HCV) infects
approximately 170 million people worldwide and is a significant cause
of liver failure. The virus is able to set up chronic infection in
about 80% of those infected, although a minority are able to clear the
virus from blood after acute exposure. Although dynamic studies of
infection are hampered by the lack of acute symptoms in most patients,
there is nevertheless accumulating evidence that multiple immune
responses are involved (8, 11, 19, 21, 24).
A role for CD4+ T-helper lymphocytes is supported
by functional and genetic linkage studies (11).
(7, 25, 28, 30). Recent studies of acute disease
have also indicated that antiviral antibody responses directed against
envelope proteins (E2) influence viral evolution and disease outcome
(9). CD8+ T lymphocytes specific for
HCV also arise early after infection (19-21) and, by
analogy with hepatitis B virus infection, theoretically could suppress
viral replication by secretion of antiviral cytokines (13). However, these populations are not sustained and
generally become difficult to detect in blood, especially when
techniques that rely on detection of gamma interferon (IFN- Patients and blood samples.
Patients were recruited from
clinics in Munich, Germany; Oxford, United Kingdom; Sydney, Australia;
and Boston, Mass. Peripheral blood mononuclear cells (PBMCs) were
prepared and frozen as previously described(19-21). For
assays comparing different time points from the same individual,
samples were thawed and stained simultaneously. Informed consent for
venipuncture was obtained in all cases. For subjects A and B (both
HLA-A*0201-positive female intravenous drug users who presented acutely
and are studied here in the most detail), seroconversion to anti-HCV
antibody positivity was determined at the time of presentation. Liver
histology was not obtained for subjects A and B, because it was not
indicated in acute disease. Their clinical details are shown in Table
1. Of the other subjects, not studied
here during acute infection, subject C also acquired virus via
intravenous drug use, subject D probably acquired the virus via sexual
contact, and subject E acquired the virus via infected blood products
(subjects 1 and 3 and 15 in reference 19). The time
of acquisition of virus was determined from clinical history and from
transfusion data. The full details of the cohorts from which these
subjects were selected, including age, tissue type, sex, PCR and
treatment status, and, where appropriate, genotype and liver
histology, have been published previously (19-21).
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.12.5550-5558.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Sustained Dysfunction of Antiviral CD8+ T Lymphocytes
after Infection with Hepatitis C Virus
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
) 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.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
) are
used (29), although they can be recovered upon stimulation
in vitro (4, 17, 27, 32). There is evidence from murine
models that failure of T-cell responses to control early-stage
infection can lead to shifts in immune-selective forces and viral
escape (6, 16). We therefore asked whether a specific
dysfunction of antiviral CD8+ T lymphocytes may
occur after infection with HCV and addressed this question by analyzing
T-lymphocyte responses directly ex vivo with peptide-major
histocompatibility complex (MHC) class I tetramers (1, 3,
12) combined with assays for lymphocyte function.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
TABLE 1.
Clinical details of subjects studied during or after
acute infection
Class I-peptide tetramers. Class I-peptide tetramers were prepared and validated exactly as previously described. The following peptides were obtained from Research Genetics (Huntsville, Ala.): NS3 peptide 1073-1081 (abbreviated here as NS3 1073; CINGVWCTV), NS5B peptide 2594-2602 (NS5 2594; ALYDVVTKL), NS4B 1406-1415 (NS4 1406; KLVALGINAV), and NS4B 1807-1816 (NS4 1807; LLFNILGGWV). The tetramers for the control Epstein-Barr virus (EBV) and cytomegalovirus (CMV) peptides restricted by HLA-A2 (EBV BMLF-1 [GLCTLVAML] and CMV pp65 [NLVPMVATV]) were validated by using peripheral blood samples from EBV- and CMV-seropositive, healthy individuals as described previously (19, 21). In screening the HCV patients, where appropriate, tetramers for two HCV epitopes restricted by HLA-B8 (HSKKKLDEL and LIRLKPTL) and two restricted by HLA-B7 (GPRLGVRAT and DPRRRSRNL) were also used, as previously described (19, 20). However, since these did not yield large tetramer-positive populations amenable to functional analysis, they are not detailed further.
Tetramer staining and functional assays.
The following
conditions were used for staining. From 0.5 to 1 million PBMCs were
coincubated with tetramer for 20 min at 37°C, followed by washing and
phenotypic staining or stimulation. The following monoclonal antibodies
(MAbs) were used: anti-CD8-PerCP, anti-CD27-fluorescein
isothiocyanate (FITC) conjugate, anti-CD45RO-allophycocyanin (APC), anti-CD45RA-FITC (all Becton Dickinson Immunocytometry Systems), anti-CC chemokine receptor 5 (CCR-5)-FITC,
anti-CD38-PC, anti-CD69-APC (all PharMingen), anti-human MHC
class II-FITC (HLA-DR,-DP, and -DQ; Dako), anti-Ki 67-FITC
(Coulter Immunotech, Marseille, France), anti-perforin-FITC
(Pharmingen), and FITC-conjugated anti-T-cell receptor (TCR) (TCR
V
1, -2, -3, -5.1, -5.2, -8, -12, -13.1, -14, -16, -17, -20, and -22;
unlabeled anti-TCR V5.3, -9, and -23 [all Coulter Immunotech]).
Unlabeled anti-TCR V antibodies were detected with
FITC-conjugated antimouse immunoglobulin (Ig) [F(ab')2; Biosource, Camarillo, Calif.].
Phorbol myristate acetate (PMA)-ionomycin stimulation was performed
exactly as described in reference 21, but the tetramer
staining was done first (20 min), and then a PMA-ionomycin mixture was
added without washing. Determination of peptide stimulation and
intracellular cytokine secretion was performed in the presence of 10 µM cognate peptide or control and 1 µg of costimulatory anti-CD28
(Pharmingen, San Diego, Calif.) and anti-CD49b antibodies (Becton
Dickinson, San Jose, Calif.) per ml (6 h). Peptide stimulation and CD69
staining were performed in the absence of costimulation (4 h). Flow
cytometric analysis was performed with a Becton Dickinson FACSCalibur
fluorescence-activated cell sorter (FACS), and analysis was performed
with CellQuest software.
CD4 proliferative assays. CD4 proliferative assays were performed with recombinant HCV proteins and tritium incorporation exactly as previously described (11).
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RESULTS |
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Abstract
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Materials and Methods
Results
Discussion
References
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Analysis of CD8+ T-lymphocyte responses ex vivo after
acute HCV infection.
We first tracked T-lymphocyte responses in a
set of four HLA-A*0201-positive patients for whom a clear date of onset
of infection was available (Table 1). Two examples (subjects A and B)
in which samples were obtained very close to the time of acquisition of virus are illustrated in detail in Fig.
1a and described in Table 1. We analyzed CD8+ T-lymphocyte responses
against four HLA-A2-restricted HCV peptides by using peptide-MHC class
II tetramers, as previously described (Fig. 1a, lower panel) (19,
21). In subject A, a significant response was observed against
NS3 1073 (CINGVWCTV [shown in Fig. 1a, middle panel])
and NS5 2594 (ALYDVVTKL), but not NS4 1406 (KLVALGINAV) or NS4
1807 (LLFNILGGWV) (not shown). In subject B, only a response to NS3
1073 was observed, but in this instance, we also had the opportunity to
compare this response with established memory responses to
HLA-A2-restricted epitopes from either EBV (GLCTLVAML) or CMV
(NLVPMVATV [0.74 and 0.25% of CD8+ lymphocytes,
respectively]).
|
) 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 (Dynamics and phenotype and of antiviral CD8+ T-lymphocyte responses over time. Interestingly, in subject A, a shift in dominance between the two detectable responses was noted over time. This occurred during a period in which the subject's blood was already negative for viral RNA by PCR, and a very similar pattern was observed under similar circumstances in a previously described case (21), as well as in cases later after infection (19, 21). The shift in numerical dominance was paralleled by a striking shift in expression of markers of activation between the two populations (Fig. 1b). The response, which peaked second (directed against NS5 2594), showed peak CD38 and class II expression 2 weeks later than the first wave of cells directed against NS3 1073. Also, both populations showed increased expression of chemokine receptor CCR5 at the time of their maximal activation, which might contribute to recruitment into the inflamed liver. The level of expression of the intracellular marker of proliferation Ki-67 was high for the first wave of cells observed, at a time when their numbers in blood were actually waning. This is consistent with either exhaustion of this response or redistribution into the liver.
Analysis of function of tetramer-positive cells ex vivo.
We
next examined the function of these virus-specific
CD8+ T-lymphocyte populations ex vivo by using an
established assay for intracellular detection of IFN- synthesis
after stimulation with PMA-ionomycin (21). These are
illustrated in Fig. 1c to e in detail for subject B, for whom an
internal comparison was available. In this individual, the level of
IFN- synthesis after stimulation was low in the HCV-specific
tetramer-positive population and was significantly lower at both time
points tested than those in the control CMV- and EBV-specific
populations (Fig. 1c). The release of IFN- in response to peptide
stimulation (a more physiological stimulus, since triggering occurs
through the TCR) showed even more profound defects (Fig. 1d) compared
to the internal control of the CMV-specific response. This dysfunction
was sustained over a period of 3 months. Consistent with this, a highly
sensitive overnight ex vivo IFN- ELISpot assay (Mabtech,
Upsalla, Sweden) performed with the same NS3 peptide was also
completely negative throughout this period (data not shown)
(18). Intermediate time points over this period showed a
very similar profile of unresponsiveness. For example, at week 7 in
subject B, at the peak of the CD4 responses (Fig. 1a, lower panels),
the IFN- ELISpot remained negative for responses against NS3 1073, as was synthesis of tumor necrosis factor alpha (TNF-) after PMA stimulation.
Analysis of CD69 upregulation in comparison to control responses. To confirm that the defect in cytokine synthesis represented a failure of triggering (rather than a switch in secretion pattern to other cytokines), upregulation of CD69 after NS3 1073 peptide stimulation in vitro was also measured at these time points, as previously analyzed (21). Again, weak responses were observed, most obviously when compared with the internal CMV control (Fig. 1e and f).
Examination of tetramer-positive responses of different
specificities and in different individuals.
The specificities of
tetramer-positive responses in different subjects were reproduced
through analyses of other responses in other patients and other
epitopes. Figure 2a illustrates cytokine staining patterns in three separate individuals in whom three distinct
epitopes (NS3 1073, NS3 1406, and NS5 2594) from HCV were targeted.
In these cases, little or no cytokine synthesis was measured after
maximal stimulation with PMA-ionomycin. This was clear by measurement
of IFN- and TNF-. These individuals were all PCR negative
at the time of study and had been so for many months. The plots
illustrated demonstrate the extremes of the range of cytokine responses
seen among HCV-specific CD8+ lymphocytes. In all
cases, the proportion of cytokine-positive cells among the
tetramer-positive population was lower than that in the
tetramer-negative CD8+ population. Exactly the
reverse result is seen in the case of CMV- and EBV-specific tetramer
populations (described below; Fig. 3b).
Again, no or very low levels of synthesis were also observed after
peptide stimulation (data not shown).
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Analysis of TCR V usage in acutely expanded HCV-specific
CD8+ T-lymphocyte populations.
We addressed whether
the HCV-specific CD8+ phenotype was the result of
expansion of a single aberrant clone by ex vivo analysis of V usage
with a panel of V-specific MAbs in the large expansions in subjects
A to D. Only in subject B was an expansion of a single V-bearing
subset seen (Fig. 2d, right panel), comprising 30% of the
tetramer-positive population at the first time point. This was not seen
in the other patients (for example, subject A [Fig. 2d, left panel])
and was not sustained in subject B, in whom the proportion
dropped to about 10% by week 14 (data not shown). Thus, the
observed phenotype of weak or absent cytokine secretion upon stimulation appears to extend across populations of
CD8+ T lymphocytes targeting distinct
epitopes and using distinct TCRs.
Analysis of lytic function and perforin staining ex vivo.
We
also had the opportunity with a single patient (subject A) to address
whether the cells identified at the peak of activation during acute
hepatitis were directly cytotoxic ex vivo. In this situation, at the
first time point, 3% of CD8+ T lymphocytes were
NS3 1073 specific and were highly activated (92% CD38 high and 64%
MHC class II high), as previously observed in other patients
(19) (Fig. 1b). Nevertheless at this time point, no
specific lysis of peptide-pulsed targets was observed in a 5-h or
extended assay for chromium release, even though the same targets were
readily lysed by a specific clone (data not shown). Consistent with
this finding, the cells were low in perforin (1.5% positive) and high
in CD27 (90% positive), a phenotype which has been associated with a
low lytic capacity and what has been described as an "immature" or
"early differentiation" phenotype (2). Of eight
responses tested for perforin staining, all were 
10% positive (mean,
3%; range, 0 to 10%) (data not shown).
Analysis of function of CD8+ T lymphocytes ex vivo in patients later after infection. We and others have previously reported that levels of virus-specific CD8+ lymphocytes (assessed by tetramer) in patients identified outside the setting of acute disease are generally very low, which renders analyses of phenotype and function technically difficult without in vitro manipulation (14, 19, 21). To further address the question of whether the dysfunction of these cells is sustained long term, we screened blood from another 56 HLA-A2-positive subjects from time points outside the first 24 months of infection. This was performed with tetramers containing the four different HLA-A2-restricted peptides exactly as used in subjects A to D (19-21). Where appropriate, we also tested subjects by using HLA-B8 and -B7 tetramers (see Materials and Methods). We obtained samples from a further three such individuals (two PCR negative and one PCR positive) with expansions of HCV-specific HLA-A2 tetramer-positive cells representing >0.1% of CD8+ lymphocytes in whom intracellular cytokine staining could be assessed after stimulation.
Examples of such an analysis (subject E) are shown in Fig. 3a and b. These show, respectively, a profound defect in synthesis of both TNF- and IFN- after peptide stimulation and a
relative defect in staining for TNF- after maximal
(PMA-ionomycin) stimulation, compared to CMV and EBV
responses. Subject E had been PCR negative after IFN-
treatment 5 years previously, and thus the defect cannot be attributed
to ongoing viremia. It was sustained over a period of 1 year, with the
relatively large HCV-specific tetramer-positive population (0.3% of
CD8+ lymphocytes) maintained in a quiescent state
(low in CD38 and HLA class II; similar to the EBV- and CMV-specific
populations; data not shown).
Internal and group comparisons between HCV-specific and control
responses.
The relative lack of cytokine secretory capacity in
HCV-specific CD8+ T lymphocytes was further
emphasized by comparisons with EBV- and CMV-specific responses within
and between individuals. In Fig. 4 (upper
panel), the synthesis of IFN- after PMA stimulation from
HCV-specific CD8+ lymphocytes is compared with
that from EBV- and CMV-specific populations in all of those individuals
in whom both responses were present. This shows a marked skewing of the
responses in favor of cytokine release from the non-HCV-specific
CD8+ populations (P < 0.002). In
some individuals (as in subject A), more than one HCV-specific response
was present, and both showed a similar phenotype by comparison with CMV
or EBV.
|
responses after PMA stimulation
are compared between HCV tetramer-positive populations and non-HCV (EBV
or CMV) populations in seven HCV antibody-positive (dark dots) and
seven control subjects (clear dots). The overall level of
responsiveness is again lower at the population level (mean, 13.5%
versus 60%; P < 0.0001). There was no significant difference between non-HCV (EBV and/or CMV) responses in HCV
antibody-positive and antibody-negative subjects.
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DISCUSSION |
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These data indicate that HCV-specific CD8+ T lymphocytes possess a distinct phenotype, which may be maintained well after virus is cleared from blood. Large populations of HCV-specific CD8+ lymphocytes are induced early and are highly activated, as judged by surface expression of appropriate marker molecules (21) (Fig. 1b), but have various degrees of impairment of antiviral functions, as assessed in vitro. These include an impaired ability to respond to peptide and to mitogen and are most obvious at the level of secretion of antiviral cytokines.
The essential differences in response dynamics or function dictating clearance versus persistence of HCV were not revealed in this study. Relative defects in cytokine secretion were seen in those who had cleared virus in the long term, and levels of intracellular perforin were universally low among HCV-specific CD8+ lymphocytes. It is possible that the essential mechanisms that control HCV in the long term lie outside of these conventional functions or indeed are displayed by some other subset of immune mediators, as has been clearly demonstrated in murine models (26). An alternative explanation is that the circulating CD8+ lymphocytes represent an unusual subset that differs from the truly functional lymphocytes. While this seems likely during chronic hepatitis infection, where compartmentalization in the liver has been observed (23), it seems unlikely in situations in which virus has been cleared and no hepatitis is detectable.
These populations differ from previously identified dysfunctional CD8+ lymphocytes in that the phenotype is sustained (21) and may occur in the presence of adequate CD4+ help (33), and the surface phenotype of the lymphocytes is otherwise normal (e.g., CD45RO high; data not shown) (22). The stability of these populations, compared with the dysfunction seen in lymphocytes undergoing exhaustion (10), indicates a long-lasting influence on function induced by the virus in an antigen-specific manner. It is possible that the inducing environment or potentially some influence on antigen-presenting cell function (15) is responsible. For example, in murine models, a similar sustained phenotype has been seen after vaccination in the presence of interleukin-10 (5). In this context, a description of "stunted" as opposed to "stunned" may be more appropriate. How this may then have an impact on the persistence of HCV remains to be determined, especially in the context of the balance with other mediators of immunity (6, 9). Methods to reverse this defect or to induce new populations of functional T lymphocytes should be explored as part of immunotherapeutic strategies and vaccine design.
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ACKNOWLEDGMENTS |
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Norbert Gruener and Franziska Lechner contributed equally to this paper.
Funding was obtained from the Wellcome Trust, the Wilhelm-Sander-Stiftung and the European Union (5th Framework, HCVacc, grant no. QLK2-CT-1999-00356), the Deutsche Forschungsgemein, the Australian Red Cross, the National Institutes of Health, and the Doris Duke Charitable Foundation.
We are grateful to Jane Collier and the staff of the hepatitis and immunology clinics at the John Radcliffe Hospital for providing patient samples to screen; Mike Bunce for tissue typing; Philip Goulder, Rod Dunbar, Richard Cornall, Victor Appay, and Andrew McMichael for helpful discussions; and A. Morse for preparation of the manuscript. We also thank Carmen Amsel, Barbara Becker, Jutta Döhrmann, and Marion Satzger for excellent technical assistance and personal encouragement.
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FOOTNOTES |
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* Corresponding author. Mailing address: Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. Phone: 01865 221335. Fax: 01865 220993. E-mail: klener{at}molbiol.ox.ac.uk.
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Journal of Virology, June 2001, p. 5550-5558, Vol. 75, No. 12
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.12.5550-5558.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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