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B Inhibition1
*
Laboratory of Experimental Immunology and Centre de Recherche Interuniversitaire en Vaccinologie, Université Libre de Bruxelles, Brussels, Belgium; and
Department of Molecular Biology and Flanders Interuniversity Institute for Biotechnology, University of Gent, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B. In parallel,
NAC was shown to down-regulate the production of cytokines by DC as
well as their surface expression of HLA-DR, CD86 (B7-2), and CD40
molecules both at the basal state and upon LPS activation. NAC also
inhibited DC responses induced by CD40 engagement. The inhibitory
effects of NAC were not due to nonspecific toxicity as neither the
viability of DC nor their mannose receptor-mediated endocytosis were
modified by NAC. Finally, we found that the addition of NAC to MLR
between naive T cells and allogeneic DC resulted in a profound
inhibition of alloreactive responses, which could be attributed to a
defect of DC as APC-independent T cell responses were not inhibited by
NAC. Altogether, our results suggest that NAC might impair the
generation of primary immune responses in humans through its inhibitory
action on DC. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (reviewed in 8 . Indeed,
NF-B activation is regulated by the redox potential of the cell
and/or by the production of radical oxygen intermediates (ROI)
(reviewed in Refs. 9–11). In addition to its direct antioxidant
properties, NAC also acts by increasing the cellular content in
glutathione (GSH), the major intracellular redox buffer 8 . The GSH content of T cells has been shown to be critical for their responses to mitogenic stimuli 12, 13, 14, 15, 16 . It has been suggested that GSH deficiency in T cells would be involved in the pathogenesis of AIDS 4, 6 and common variable immunodeficiency 17 , and, therefore, that NAC may improve T cell functions in these conditions. However, the stimulatory effects of NAC on human T cells have only been documented in systems in which T cell activation does not depend on accessory signals delivered by APC 12, 13, 14, 15, 16 .
During a primary immune response, the activation of T cells
depends on their interactions with dendritic cells (DC), a highly
specialized population of APC that express constitutively NF-B
18, 19, 20, 21, 22, 23, 24 . DC have the unique ability to stimulate naive T cells through
the expression on their membrane of high levels of MHC class II
molecules, which are critical for Ag presentation to Th cells as well
as costimulatory molecules (i.e., B7 molecules) that deliver accessory
signals required for T cell activation 18, 19 .
To get further insight into the immune effects of NAC, we determined
its effects on human DC, paying particular attention to NF-B
activity, cytokine production, and expression of costimulatory
molecules both at the basal state and upon activation induced by either
LPS or CD40 engagement 25, 26, 27, 28, 29 . Finally, we determined the effect of
NAC on the ability of DC to elicit a primary alloreactive T cell
response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Culture medium for the generation of DC consisted in RPMI 1640 (Life Technologies, Paisley, Scotland) supplemented with 2 mM L-glutamine, 20 µg/ml gentamicin, 50 µM 2-ME, 1% nonessential amino acids (Life Technologies), and 10% FBS (Myoclone; Life Technologies). For all subsequent experiments, culture medium was devoid of 2-ME. rIL-4 was purchased from Genzyme (Cambridge, MA). Recombinant granulocyte-macrophage (GM)-CSF was obtained from Schering-Plough (Brussels, Belgium). NAC, L-buthionine sulfoximine (BSO), and LPS from Escherichia coli (serotype 0128:B12) were obtained from Sigma (Bornem, Belgium). NAC was dissolved in RPMI 1640, and pH was adjusted to 7.4 by the addition of NaOH.
Cell preparations
DC were generated from PBMC as described by Romani et al. 30 . Briefly, PBMC from healthy volunteers were isolated by density centrifugation of heparinized blood on Lymphoprep (Nycomed, Oslo, Norway), resuspended in culture medium, and allowed to adhere to 6-well plates. After 2 h at 37°C, nonadherent cells were removed and adherent cells were cultured in 3 ml of medium containing GM-CSF (800 U/ml) and IL-4 (500 U/ml). Every 2 days, 300 µl of medium were removed and replaced by the same volume of fresh medium containing 2400 U of GM-CSF and 1500 U of IL-4. After 7 days of culture, DC were harvested, washed, and used for subsequent experiments. The resulting cell preparation contained >90% DC as assessed by morphology and FACS analysis. T lymphocytes were purified from PBMC using Lympho-Kwik (One Lambda, Los Angeles, CA); they were >90% pure as assessed by FACS. Naive CD45+ CD4+ T cells were purified in two steps using magnetic cell separation columns and Ab mixture (Miltenyi Biotech, Auburn, CA): an initial step of negative selection of CD4+ T cells was followed by a second step of negative selection of CD45RA+ cells. CD45RA+ CD4+ T cells were >95% pure as assessed by FACS analysis.
DC cultures
A total of 5 x 105 DC were cultured during 24 h in a 24-well plate in 1 ml of medium with or without NAC. To test the role of GSH in the effects of NAC, 1 mM BSO was added 1 h prior the addition of NAC. For experiments assessing the effects of NAC on DC maturation, DC were incubated during 24 h in medium supplemented with 10 ng/ml LPS or during 72 h in the presence of mouse fibroblasts transfected with the human CD40 ligand (CD40L) gene (a kind gift from Dr. Kris Thielemans, Vrije Universiteit Brussel, Belgium) together with NAC. After the incubation period, cells were harvested for phenotypic analysis by flow cytometry and supernatants were harvested for determination of cytokine levels by ELISA.
T cell stimulation
A total of 2 x 105 purified T cells or naive CD45RA+ CD4+ T cells were stimulated in a 96-well plate either by 7 x 103 allogenic irradiated DC (DC:T ratio of 1:30) or by coated OKT3 mAb (5 µg/ml) (Ortho Biotech, Raritan, NJ) plus anti-CD28 mAb (1 µg/ml; Immunotech, Marseille, France) in the presence or the absence of NAC. To compare the effects of NAC on APC-dependent vs APC-independent stimulation of purified T cells in the first experiments using purified T cells, we tested increasing doses of NAC in stimulation experiments conducted during 3 days. We then assessed the effects of optimal concentration of NAC on primary MLR using naive T cells during various incubation periods. After the incubation period, supernatants were harvested for determination of cytokine levels and [3H]thymidine was added during 8 h to assess cell proliferation.
Cytokine assays
IL-6, IL-8, TNF-
, and IL-12 (p40) were measured by ELISA kits
from Biosource Europe (Fleurus, Belgium). IFN-
and IL-5 were
measured using ELISA kits from Chromogenix (Mölndal, Sweden) and
PharMingen (San Diego, CA), respectively.
Immunophenotyping of DC
Cells were washed in PBS supplemented with 1% BSA, 0.1% NaN3, 10% pooled human serum, and incubated for 30 min at 4°C with one of the following mAbs: phycoerythrin (PE)-conjugated anti-HLA-DR IgG2a mAb (Becton Dickinson, Mountain View, CA), PE-conjugated anti-CD80 IgG1 mAb (B7-1; Becton Dickinson), PE-conjugated anti-CD86 (B7-2) IgG2b mAb (PharMingen, San Diego, CA), FITC-conjugated anti-CD40 IgG1 mAb (Biosource International, Camarillo, CA), or corresponding isotype-matched control mAbs. Cell fluorescence was then analyzed using a FACScan flow-cytometer (Becton Dickinson).
Apoptosis detection
A total of 2 x 105 cells were incubated with 5 µl annexin V-FITC in binding buffer (Bender MedSystems, Vienna, Austria) during 10 min, then washed and resuspended in binding buffer before the addition of 5 µg/ml propidium iodide (PI). Cells in early apoptosis (annexin V-positive cells), cells in late apoptosis (annexin V-positive and PI-positive), and necrotic cells (PI-positive cells) were then quantified by FACS.
Mannose receptor-mediated endocytosis evaluation
DC were washed in LPS-free PBS and resuspended in medium buffered with 25 mM of HEPES and containing 0.5 µg/ml FITC-Dextran (Molecular Probe, Eugene, OR). After 15 min of incubation at 37°C or 0°C (as negative control), cells were washed four times with cold PBS prior FACS analysis.
Cellular GSH assay
A total of 106 DC were washed in PBS and sonicated. Proteins were then precipitated with 200 µl metaphosphoric acid 5% and centrifuged at 10,000 rpm for 2 min. Total GSH was measured in the supernatant by reduction with DTT, derivatization with monobrobimane, and separation by HPLC (adapted from 31 .
Electrophoretic mobility shift assay
DC were incubated during 2 h in the different conditions
tested (medium alone, 25 mM NAC, 10 ng/ml LPS, or LPS plus NAC). Cells
were then harvested and washed twice in cold PBS. Total cell extracts
were prepared by resuspending the cell pellet in Totex buffer (20 mM
HEPES, 350 mM NaCl, 20% glycerol, 1% NP40, 1 mM MgCl2, 0.5 mM EDTA,
0.1 mM EGTA, 2 mM Pefabloc, 5 mM DTT, and 0.15 IU Aprotinin) during 15
min on ice. After centrifugation, the supernatant was collected and
stored at -70°C. NF-B binding activity of the protein extract was
tested using an oligonucleotide from the murine Ig enhancer that had
the following sequence: 5'-AGC TAG AGG GGA CTT TCC GAG AGG-3' and was
end-labeled with [-32P]ATP by using Klenow enzyme
(Boerhinger Mannheim, Mannheim, Germany). For the binding reaction, 30
µg of the extract were added to a reaction mixture containing 2 µg
poly(dI-dC) (Pharmacia, San Diego, CA), 20 µg BSA, 4% Ficoll 400, 20
mM HEPES, 60 mM KCl, 2 mM DTT, and 10,000 cpm of
[32P]-labeled oligonucleotide in a final volume of 20
µl and were incubated at room temperature for 15 min. The free and
protein-bound oligonucleotides were separated by electrophoresis on a
4% polyacrylamide gel in a 0.5x Tris-borate EDTA buffer. After
electrophoresis, the gel was dried and exposed to a PhophorImager
screen (Molecular Dynamics, Sunnyvale, CA).
Statistical analysis
Data were compared using the nonparametric Wilcoxon’s paired test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B in
human DC
As DC express constitutively the transcription factor NF-B,
which regulates the expression of many genes encoding immune and
inflammatory proteins, we first evaluated the effect of NAC on NF-B
activity in DC both at the basal state and upon stimulation by LPS. The
concentration of NAC (25 mM) used in this first series of experiments
was chosen according to previous studies on other cell types 1, 5 . As
shown in Fig. 1
, we observed that DC
treatment with LPS clearly increased the activity of NF-B and that
NAC inhibited the constitutive as well as the LPS-induced NF-B
activity. Specificity of NF-B complex was established using excess
unlabeled NF-B probe, which competed successfully for NF-B
binding, while a nonspecific competitor (AP-1 probe) did not.
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To determine whether the inhibitory action of NAC on NF-B
activity was paralleled by modifications of the phenotype of DC, we
tested the effects of NAC on the expression of surface molecules
involved in the APC function of DC. As shown in Fig. 2, NAC clearly inhibited the expression
of HLA-DR, B7-2 (CD86), and CD40, while leaving the expression of B7-1
(CD80) unchanged. These effects of NAC were observed in presence as
well as in absence of IL-4 and GM-CSF (data not shown).
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As DC maturation is an essential process during which DC acquire
optimal immunostimulatory properties, we examined the influence of NAC
on DC responses to LPS or CD40 ligation, which are major stimuli for DC
maturation 25, 26, 27, 28, 29 . As shown in Table I,
the enhanced secretion of IL-6, IL-8, IL-12, and TNF- induced by LPS
was inhibited by NAC in a dose-dependent manner; a maximal effect was
achieved at a concentration of 25 mM. NAC also inhibited CD40L-induced
cytokine secretion, although less efficiently. As shown in Fig. 2
, NAC
simultaneously inhibited the up-regulation of HLA-DR, B7-2, and CD40
associated with LPS-induced activation. The induction by LPS of CD83,
an established marker of DC maturation 32, 33 , was also prevented by
NAC.
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To exclude a cytopathic effect of NAC on DC, we first evaluated DC
viability using PI and annexin V staining. As shown in Table II, treatment of DC with NAC did not
modify the percentages of apoptotic and/or necrotic cells. Furthermore,
we found that NAC did not interfere with the ability of DC to
internalize FITC-dextran (Fig. 3),
indicating preservation of their ability of mannose receptor-mediated
endocytosis, which is an active metabolic process of immature DC 25 .
In addition, NAC prevented the down-regulation of this process induced
by LPS (Fig. 3).
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As NAC can act both through its scavenging properties of ROI and
as a precursor for GSH synthesis, we evaluated the effects of NAC in
the presence of BSO, an agent that prevents neosynthesis of GSH by
inhibiting the -glutamylcysteine synthetase 34 . As shown in Table III, the inhibitory effects of NAC on the
constitutive expression of B7-2 and CD40 were not affected by the
presence of BSO at a concentration preventing the increase in GSH
content induced by NAC. Similarly, BSO did not affect the inhibition of
LPS responses by NAC (data not shown).
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As NAC down-regulates the expression of molecules that are
critical for the stimulation of naive T cells by DC and renders DC
refractory to maturating stimuli, we compared the effects of NAC on T
cell responses induced either by allogeneic DC or by a combination of
anti-CD3 and anti-CD28 Abs, the latter activation system being
APC-independent. As shown in Fig. 4, the
addition of increasing doses of NAC to MLR between purified T cells and
irradiated allogeneic DC inhibited the proliferative response as well
as the production of IFN- and IL-5 in a dose-dependent manner. These
effects were observed in six independent experiments
(p < 0.05 beyond 1.5 mM NAC for proliferation
and IFN- production and beyond 3 mM NAC for IL-5 production). In
contrast, T cell responses to anti-CD3 and anti-CD28 Abs were
either increased (p < 0.05 for IFN-
production when NAC is added at concentrations ranging from 1.5–12 mM)
or not modified by the addition of NAC (Fig. 4).
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) as
well as the secretion of cytokines (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activity in DC and in parallel down-regulates the
expression of surface molecules known to be critical for their APC
function. These molecules include HLA-DR involved in the presentation
of antigenic peptides to CD4+ T cells, B7-2, a
costimulatory molecule acting as a ligand for CD28 expressed at the T
cell membrane 35 , and CD40, which transduces activation signals
required for the up-regulation of B7 molecules and the induction of
IL-12 synthesis by DC in the early phase of the immune response 36, 37 . Our data confirm previous observations showing that DC express
constitutively NF-B 20, 21, 22, 23, 24 and suggest that NF-B activity is
required directly or indirectly for the regulation of the expression of
genes that are critical for their function.
The inhibitory effects of NAC on NF-B activity have been attributed
in other cell types to its direct scavenging properties of ROI and/or
to its ability to alter the redox potential of the cell to a more
reduced one, either directly by the presence of a thiol group or
indirectly by increasing the synthesis of GSH 7, 8, 9, 10, 11 . In this study,
it appears that the inhibitory effects of NAC on DC are not due to a de
novo synthesis of GSH as they were maintained in the presence of BSO,
an inhibitor of GSH synthesis. Accordingly, previous data have
demonstrated similar GSH-independent inhibitory effects of NAC on TNF
production by Kupffer cells 38 , as well as on HIV transcription and
replication in T cells 4, 39 .
Maturation of DC is a critical process as only mature DC are able to
induce optimal activation of naive T cells. During this process, DC
lose their ability to capture and process Ags, increase their
expression of MHC class II and costimulatory molecules, and up-regulate
their production of cytokines 25, 26, 27, 28, 29 . In addition, maturation is
closely associated with surface expression of CD83, the function of
which is still unknown 32, 33 . In vivo, schematically, maturation of
DC is initiated in nonlymphoid tissues upon exposure to inflammatory
molecules such as LPS and is achieved in lymph nodes upon CD40
engagement by CD40L-expressing T cells. NAC was found to strongly
inhibit DC maturation as reflected by its inhibitory effects on
cytokine synthesis, MHC class II, B7-2, and CD40 up-regulation,
induction of CD83 expression, and down-regulation of mannose
receptor-mediated endocytosis induced by LPS. Moreover, we observed
that LPS-induced maturation of DC was associated with increased
activity of NF-B and that NAC also inhibited this effect of LPS on
DC. Finally, NAC did also inhibit the effects of CD40 engagement on the
stimulation of cytokine production and costimulatory molecule
expression (data not shown). The functional relevance of the effects of
NAC on DC was established during MLR experiments in which we observed
that NAC inhibits the ability of DC to stimulate alloreactive T cells.
Indeed, the T cell proliferative responses as well as the synthesis of
cytokines of both Th1-type (IFN-) and Th2-type (IL-5) were decreased
by NAC. The suppressive effect of NAC was especially pronounced when
naive CD45RA+ CD4+ T cells were used as
responder cells. This is consistent with the fact that the activation
of naive T cells is strongly dependent on costimulatory signals
delivered by DC 18, 19, 40, 41 . Interestingly, Peterson et al. 42
recently showed that GSH depletion of murine spleen cells inhibits
their ability to elicit Th1-type responses while favoring Th2-type
responses. It is possible that the effects of GSH depletion in this
model are due to its action on other APC than DC. Moreover, GSH
depletion should not be considered as a mirror of NAC treatment as
certain effects of NAC do not involve GSH replenishment. Indeed, as
already mentioned, the deactivating effects of NAC in DC, but also in
other systems 4, 38, 39 , were found to be independent of an increase
in intracellular GSH. Our data corroborate previous observations made
by Chaudhri et al. 43 indicating that different types of
antioxidants inhibited primary alloantigen-induced T cell responses,
although the influence of these compounds at the DC level was not
considered in this mouse model.
Previous studies have clearly established that T cell hyporesponsiveness observed in various conditions including AIDS 4, 6 , common variable immunodeficiency 17 , and ageing 44 are related to a decrease in T cell GSH content, leading to propose GSH supplementation using NAC to enhance immune functions in these disorders. Our observation that NAC inhibits primary human T cell responses elicited by DC indicates that this drug should be considered as a double-edged sword when administered to immunodeficient patients. On the other hand, we suggest that the immunosuppressive effects of NAC at the DC level might be exploited to prevent pathogenic immune responses such as allograft rejection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michel Goldman, Hôpital Erasme, Department of Immunology, 808 route de Lennik, B-1070 Brussels, Belgium. E-mail address:
3 Abbreviations used in this paper: NAC, N-acetyl-L-cysteine; DC, dendritic cell; ROI, radical oxygen intermediates; GSH, glutathione; BSO, L-buthionine sulfoximine; CD40L, CD40 ligand; PI, propidium iodide; GM, granulocyte-macrophage; PE, phycoerythrin.
Received for publication August 19, 1998. Accepted for publication November 12, 1998.
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B and transcription of human deficiency virus. Proc. Natl. Acad. Sci. USA 87:9943.B transcription factor and HIV-1. EMBO J. 10:2247.[Medline]
B in the immune system. Annu. Rev. Immunol. 12:141.[Medline]
B: an oxidative stress responsive transcription factor of eukaryotic cells (a review). Free Radical Res. Comm. 17:221.
B activation. Free Radical Biol. Med. 22:1115.[Medline]
B/rel and Sp1 transcription factors in human immunodeficiency virus 1-induced, dendritic cell-T-cell syncitia. Proc. Natl. Acad. Sci. USA 92:10944. promoter in the murine dendritic cell line 18 and the murine mast cell line CPII is differently regulated. J. Immunol. 157:2645.[Abstract]
B activation in hemopoeitic progenitor cells. J. Immunol. 160:1224. from isolated rat Kupffer cells. Biochem. J. 320:1005.
B activity by cysteine and cysteine derivatives. AIDS 5:497.-503. [Medline]
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