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IMMUNOBIOLOGY
From the Divisions of Oncology and of Gastroenterology
and Hepatology, Department of Medicine, Stanford University Medical
Center, Stanford, CA.
Dendritic cells (DCs) are important for the initiation of immune
responses to foreign antigens. Their antigen uptake and presentation capacities enable them to prime and activate T cells. Immature DCs
capture antigens; however, they must be activated to mature before
serving as efficient antigen-presenting cells. The antigen-presenting capacity of DCs can be diminished during viral infection and as a
consequence of tumor formation. Chronic infection with hepatitis C
virus (HCV) has been shown to affect the allostimulatory function of
DCs. In this study, it is demonstrated that monocyte-derived DCs from
patients with chronic HCV infection do not respond to maturation
stimuli. Instead, they maintain their immature phenotype, reflected by
the pattern of cell surface markers and by their continued capacity to
uptake antigen. Moreover, their allostimulatory abilities are impaired
compared with those of mature DCs derived from healthy donors. To
investigate a possible correlation between viral clearance and this DC
maturation defect, patients with resolved HCV infection after a course
of antiviral therapy were studied. Results demonstrate that DCs from
patients who cleared HCV behaved like DCs from healthy donors: in
response to maturation stimuli, they decrease antigen uptake,
up-regulate expression of appropriate surface markers, and are potent
stimulators of allogeneic T cells.
(Blood. 2001;97:3171-3176) Dendritic cells (DCs) are important for the
initiation of immune responses to foreign antigens because of their
"professional" competence to capture and present antigen to T
cells. The 2 functions, antigen uptake and presentation, are temporally
and spatially separated. Thus, after antigen internalization, the DCs
themselves undergo a process of maturation, migration, and relocation
(for review, see Bell et al1). During maturation, DCs
up-regulate major histocompatibility complex (MHC), adhesion, and
costimulatory molecules, including CD80 (B7.1), CD86 (B7.2), CD54
(ICAM-1), CD58 (LFA-3), CD11a, CD11c, and CD40, whereas they
down-regulate the expression of Fc and mannose receptors.2
Mature DCs also secrete high levels of interleukin-12 (IL-12), a
Th-1-polarizing cytokine that promotes the maturation of cytotoxic T
cells (CTLs).3
Several viruses, such as herpes simplex virus,4 measles
virus,5 and Epstein-Barr virus, have been shown to
diminish DC function. Recently, hepatitis C virus (HCV) infection has
also been shown to affect the function of DCs. Compared to
monocyte-derived DCs from healthy donors, DCs from patients with
chronic HCV infection showed impaired ability to stimulate allogeneic T
cells and to produce interferon Hepatitis C virus causes an often inapparent acute infection that is
cleared only in a minority of patients.8 Patients who are
able to clear the virus mount a vigorous T-cell response. Spontaneous
viral clearance is correlated with both HCV-specific, IFN- Because DCs are essential for T-cell activation, we questioned whether
viral clearance was affected by their abilities to process and present
antigen. We therefore compared DCs from chronically infected patients
to those from patients who cleared the virus after a course of
antiviral therapy and to those of healthy donors. DCs were generated in
a 2-step protocol.15 First, monocytes were isolated from
peripheral blood mononuclear cells (PBMCs) and cultured in the presence
of IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF)
for 5 days. Subsequently, immature DCs were stimulated to mature with
tumor necrosis factor- We demonstrate that monocytes and immature DCs from patients with
chronic HCV infection do not differ in phenotype or function from those
derived from healthy donors. Yet DCs from chronically infected patients
cannot be stimulated to mature. They resemble immature DCs from healthy
donors. However, DCs from patients whose HCV infection resolves after
antiviral therapy behave like DCs from healthy donors; they can be
stimulated to mature and to function as potent stimulators of
allogeneic mixed leukocyte reaction (mLR).
Donors
Cell culture
Immunophenotyping Antibodies used for cell surface staining included CD3, CD11c, CD14, CD19, CD40, CD54, HLA-DR (Becton Dickinson, San Jose, CA), CD1a, CD40, CD86 (Pharmingen, San Diego, CA), and CD83 (Immunotech, Marseilles, France). All antibodies were mouse monoclonal antibodies conjugated to fluorescein isothiocyanate (FITC) or phycoerythrin (PE). An irrelevant mouse isotype control (Becton Dickinson) was included in the analysis. Data acquisition and analysis were performed on a FACS Scan flow cytometer (Becton Dickinson, Mountain View, CA) using Cellquest software.Antigen uptake Antigen uptake by DCs was performed as previously described.2 Briefly, 50 µg/mL FITC-labeled bovine serum albumin (BSA-FITC; Sigma, St Louis, MO) was added to 1 × 106 cells at 37°C. Uptake of the same concentration of BSA-FITC at 4°C served as a negative control. Both groups were incubated for 30 minutes in the dark. After incubation, cells were washed twice in cold PBS plus 1% BSA and analyzed by FACS. Data represent the difference in mean fluorescence intensity (MFI) of DCs after BSA-FITC uptake at 37°C and at 4°C.Allogeneic mixed leukocyte reaction The stimulatory ability of DCs was assessed in an allogeneic mLR. For all assays, PBMCs from the same healthy donor served as a source of responder cells. Donor PBMCs were isolated by Ficoll-Hypaque density gradient centrifugation, as previously described, and resuspended in fetal calf serum (FCS) containing 10% dimethyl sulfoxide (Sigma), and aliquots were frozen in liquid nitrogen. Responder PBMCs were thawed immediately before use, washed, and resuspended in RPMI + 10% FCS and plated at 1 × 105 responder cells per well. Dendritic cells (day 7) were treated with 25 µg/mL mitomycin C (Sigma) at 37°C for 30 minutes and subsequently washed 3 times in media (RPMI + 10% FCS) before plating. Decreasing numbers of DCs were mixed with responder PBMCs, as indicated in the legend to Figure 3. DCs cultured in the absence of responder cells served as control for background proliferation. Cells in triplicate wells of a 96-well flat-bottom plate (Corning, Corning, NY) were cultured for 5 days and subsequently pulsed with 1 µCi [3H] thymidine during the last 16 hours of culture. [3H] Thymidine incorporation was measured using a liquid scintillation counter (Wallac-Perkin-Elmer, Wallac, Finland).
Changes in surface marker expression in response to stimulation
with TNF- We then analyzed the maturation of immature DCs from the 3 groups. DCs
from healthy donors displayed characteristic features of mature myeloid
DCs, including veiled morphology by light microscopy, nonadherence to
plastic, and positivity for a distinct set of cell surface markers.
However, these characteristics were not observed in DC cultures
generated from patients with chronic HCV infection. As shown in a
representative example, (Figure 1A, left panels), day 7 DCs from a healthy donor expressed the mature DC markers
CD1a and CD83. These DCs also expressed high levels of MHC class II,
the adhesion molecule CD54, and the costimulatory molecule CD86. In
contrast, DCs derived from a patient with chronic infection expressed
lower levels of these markers, though they were cultured under
identical conditions (Figure 1A, middle panels). Cumulative data
regarding the maturation status of DCs derived from 15 patients with
chronic HCV infection and 13 healthy donors are shown in Figure 1B.
These results demonstrate that the percentage of cells expressing
mature DC markers is reduced in patients with chronic HCV infection in
comparison with healthy donors. Noticeably, the differences in the
percentages of CD1a+ cells (70% vs 40%;
P
Antigen uptake by dendritic cells Immature DCs capture antigen efficiently and yet lose this capacity on maturation.16 Therefore, the decrease in antigen uptake has been used to monitor DC maturation.17 Because DCs of patients with chronic HCV infection showed an immature phenotype, we used this functional assay and tested the uptake of a labeled antigen, (BSA-FITC) by the DCs of the 3 groups. As expected, DC on day 5, before stimulation with TNF- , captured BSA-FITC at 37°C
but not at 4°C (Figure 2A, day 5).
Immature DCs from a healthy donor (Figure 2A), from a patient with
chronic HCV infection (Figure 2B), and from a patient whose HCV
infection resolved (Figure 2C) internalized comparable amounts of the
antigen. However, after stimulation with TNF-, only DCs from
patients with chronic HCV infection continued to capture BSA-FITC
(Figure 2B, day 7). Cumulative results of antigen uptake on day 5 by
DCs obtained from healthy donors or from patients with chronic or
resolved HCV infection are similar for all 3 groups (Figure 2D, day 5)
(P = .32 for HCV-infected patients vs healthy donors;
P = .11 for healthy donors vs patients with resolved HCV
infection). In contrast, after TNF- stimulation (day 7), DCs from
HCV-infected patients continued to capture antigen at levels comparable
to those on day 5 (P = .19) and significantly higher than
DCs on day 7 from healthy donors (P = .02) and patients with resolved HCV infection (P = .03). After the
maturation stimulus, DCs from healthy donors and patients with resolved
HCV infection decreased their antigen uptake to the same low level
(P = .85). Thus, DCs from healthy donors and from patients
who cleared HCV infection down-regulated antigen capture on stimulation
with TNF-. In contrast, though stimulated to mature for 2 days with
TNF-, DCs from patients with chronic HCV infection continued to
uptake antigen.
Immunostimulatory properties of dendritic cells in allogeneic mLR DCs increase their antigen presentation capabilities on maturation because of the up-regulation of MHC class I and II and the costimulatory molecules on their cell surfaces. Thus, their state of maturation reflects their ability to stimulate allogeneic mLR. To test the allostimulatory potential of mature (day 7) DCs in this study, we used PBMCs from a single healthy donor as responders in all assays. Cells were incubated for 5 days, and cell proliferation was assessed by [3H] thymidine incorporation. Figure 3 summarizes the results of these assays. Individuals are represented by single symbols, and group means are depicted as horizontal bars at the indicated stimulator-to-responder ratio. Stimulatory capacity of DCs from HCV-infected patients was significantly decreased in comparison with DCs from healthy donors and with those from patients who had cleared the virus at all 4 stimulator-to-responder ratios (P .02). No difference was observed between healthy donors and patients who had cleared HCV
infection. In summary, significantly decreased allostimulatory capacity
was observed for DCs from patients with chronic HCV infection compared
with DC derived from healthy controls. However, DCs from patients whose
HCV infection resolved showed allostimulatory capacity similar to that
of healthy controls.
Chronic HCV infection is a major public health problem, with more than 100 million people worldwide estimated to be infected with the virus.8,18 The clinical course of HCV is highly variable. In most patients, the initial infection remains clinically asymptomatic, and neither the time nor the route of infection is known. HCV infection becomes chronic in 85% of patients and resolves only in 15% of patients.19,20 The virus achieves persistence in most patients by circumventing both humoral and cellular immune responses. However, the mechanism applied remains to be detected. Thus, better understanding is needed of how antiviral immune responses are modulated in acute and chronic HCV infection. Viral clearance has been correlated with a vigorous T-cell response encompassing a large number of viral epitopes. This was shown in infected humans21 and chimpanzees experimentally infected by the virus.22 In contrast, in patients and chimpanzees with chronic HCV, the virus elicits only a weak T-cell response.21,22 Therefore, a defective antiviral immune response might be an important reason for HCV persistence. Induction of an effective immune response requires the active participation of host APCs, the most potent of which are DCs.23 Strategies using DCs have been effective in overcoming self-tolerance when they are used as antitumor vaccines.24-26 To date, few studies have analyzed the role of DCs in HCV infection, and these studies tested only DCs from patients with chronic HCV infection. The stimulatory capacity of such DCs was shown to be significantly decreased in an allogeneic mLR when compared to those of healthy donors. Our results confirm these earlier findings by demonstrating a diminished ability of DCs from chronic HCV carriers to stimulate allo-mLR. In addition, we investigated the underlying cause for this functional
impairment and have shown that DCs from patients with chronic HCV
infection have a maturation defect. Unlike DCs from healthy donors who
respond to TNF- To determine whether this maturation impairment was associated with
viral persistence, we investigated DCs from 8 patients whose HCV
infection resolved after treatment (Table 1). Our data clearly
demonstrate that DCs generated from these patients behaved phenotypically and functionally like those obtained from healthy controls. This is the first study to analyze DCs from patients who
cleared viral infection. It demonstrates that their responses to
maturation stimuli and their functional abilities are identical to
those of DCs from healthy donors. This might suggest that the defect
seen in the chronically infected patients is limited to the period of
viral infection but can be reversed after viral clearance.
Alternatively, a possibility exists that these patients' DCs matured
normally Viral clearance of patients whose HCV infection resolved has frequently been associated with vigorous T-cell responses. Moreover, CD4+ and CD8+ T cells that were active in clearing the acute phase of the infection were maintained after viral clearance.9-13 Could the potency of the T-cell response depend on efficient antigen presentation? Increasing T-cell responses have been correlated with the maturation stage of DCs and the generation of tumor immunity. DCs expressing high levels of costimulatory and adhesion molecules were able to induce protective tumor immunity against a poorly immunogenic tumor. Mature DCs induced the most potent response.27 It remains to be determined whether the correlation between viral clearance and effective antigen presentation by DCs, seen in this study, is also correlated with more potent antiviral T-cell responses. DC maturation and function are modulated by their microenvironment. For example, DCs require T cells for functional maturation in vivo and in vitro,28-30 yet anergic T cells can inhibit the allostimulatory capacity of DCs and down-regulate MHC class II, CD80, and CD86 on their surfaces.31 The fact that anergic T cells can negatively influence DC function is important in the context of HCV. HCV-specific CD8+ cells have been detected in the circulation of patients with chronic HCV infection. However, it has recently been shown that 90% of these CD8+ cells were negative for the activation markers CD38 and CD69. This anergic phenotype was maintained despite stimulation by their specific antigen.32 Thus, it is possible that the impaired maturation of DCs, seen in this study, is a consequence of their interaction with anergic T cells. In summary, the immune response in patients with chronic HCV infection was previously shown to be impaired at the effector cell level. Here we demonstrate that impaired maturation of DCs correlated with persistent HCV infection. In contrast, patients who cleared the virus have normal DCs. In the future, it will be important to determine whether the virus affects DCs directly or whether the impaired phenotype and function are secondary to the chronicity of infection.
We thank Lucinda Porter and Susanna Lam for their help with blood sample collection and Debra K. Czerwinski for her help with immunophenotyping. We thank Ron Levy, John Timmermann, Elizabeth R. Quinn, and Mike Flint for reviewing the manuscript.
Submitted November 14, 2000; accepted January 19, 2001.
Supported by National Institutes of Health grant CA34233 (S.L.). E.K. is funded by the Stanford Hutchinson Program. S.A.-G. is supported by a grant from Dr Mildred Scheel Stiftung fuer Krebsforschung, Germany.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Shoshana Levy, Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5151; e-mail: levy{at}cmgm.stanford.edu.
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I. S. Ludwig, A. N. Lekkerkerker, E. Depla, F. Bosman, R. J. P. Musters, S. Depraetere, Y. van Kooyk, and T. B. H. Geijtenbeek Hepatitis C Virus Targets DC-SIGN and L-SIGN To Escape Lysosomal Degradation J. Virol., August 1, 2004; 78(15): 8322 - 8332. [Abstract] [Full Text] [PDF]
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T. Laskus, M. Radkowski, J. Jablonska, K. Kibler, J. Wilkinson, D. Adair, and J. Rakela Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages Blood, May 15, 2004; 103(10): 3854 - 3859. [Abstract] [Full Text] [PDF]
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D. D. Anthony, N. L. Yonkers, A. B. Post, R. Asaad, F. P. Heinzel, M. M. Lederman, P. V. Lehmann, and H. Valdez Selective Impairments in Dendritic Cell-Associated Function Distinguish Hepatitis C Virus and HIV Infection J. Immunol., April 15, 2004; 172(8): 4907 - 4916. [Abstract] [Full Text] [PDF]
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R. S. Longman, A. H. Talal, I. M. Jacobson, M. L. Albert, and C. M. Rice Presence of functional dendritic cells in patients chronically infected with hepatitis C virus Blood, February 1, 2004; 103(3): 1026 - 1029. [Abstract] [Full Text] [PDF]
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M. Radkowski, A. Bednarska, A. Horban, J. Stanczak, J. Wilkinson, D. M. Adair, M. Nowicki, J. Rakela, and T. Laskus Infection of primary human macrophages with hepatitis C virus in vitro: induction of tumour necrosis factor-{alpha} and interleukin 8 J. Gen. Virol., January 1, 2004; 85(1): 47 - 59. [Abstract] [Full Text] [PDF]
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J. P. Gardner, R. J. Durso, R. R. Arrigale, G. P. Donovan, P. J. Maddon, T. Dragic, and W. C. Olson L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus PNAS, April 15, 2003; 100(8): 4498 - 4503. [Abstract] [Full Text] [PDF]
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C. W. Y. Chan, L. S. Kay, R. G. Khadaroo, M. W. C. Chan, S. Lakatoo, K. J. Young, L. Zhang, R. M. Gorczynski, M. Cattral, O. Rotstein, et al. Soluble Fibrinogen-Like Protein 2/Fibroleukin Exhibits Immunosuppressive Properties: Suppressing T Cell Proliferation and Inhibiting Maturation of Bone Marrow-Derived Dendritic Cells J. Immunol., April 15, 2003; 170(8): 4036 - 4044. [Abstract] [Full Text] [PDF]
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M. Jinushi, T. Takehara, T. Kanto, T. Tatsumi, V. Groh, T. Spies, T. Miyagi, T. Suzuki, Y. Sasaki, and N. Hayashi Critical Role of MHC Class I-Related Chain A and B Expression on IFN-{alpha}-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection J. Immunol., February 1, 2003; 170(3): 1249 - 1256. [Abstract] [Full Text] [PDF]
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B. Saunier, M. Triyatni, L. Ulianich, P. Maruvada, P. Yen, and L. D. Kohn Role of the Asialoglycoprotein Receptor in Binding and Entry of Hepatitis C Virus Structural Proteins in Cultured Human Hepatocytes J. Virol., December 6, 2002; 77(1): 546 - 559. [Abstract] [Full Text] [PDF]
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P. Sarobe, J. J. Lasarte, N. Casares, A. Lopez-Diaz de Cerio, E. Baixeras, P. Labarga, N. Garcia, F. Borras-Cuesta, and J. Prieto Abnormal Priming of CD4+ T Cells by Dendritic Cells Expressing Hepatitis C Virus Core and E1 Proteins J. Virol., April 16, 2002; 76(10): 5062 - 5070. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
(IFN-
) and 13 healthy donors (
).
Data are expressed as mean percentage of positive cells ± SD
(left panels) and mean fluorescence intensity ± SD (right
panels). *P 
MFI) on
day 5 and day 7 for all persons is shown in panel D. Single symbols
represent individuals: 
, patient with resolved HCV infection. Horizontal
bars represent group means. *P 
hence their ability to eliminate the virus. Unfortunately,
earlier blood samples from these patients are not available to test
this possibility.