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*
Laboratoire Universitaire d’Hématologie et de Biologie des Cellules Sanguines, Institut National de la Santé et de la Recherche Médicale CRI 9606-UPRES EA 22-33, Rennes, France;
Etablissement de Transfusion Sanguine de Bretagne, Rennes, France;
Institut National de la Santé et de la Recherche Médicale U456 Université de Rennes I, Rennes, France; and
§
Institut National de la Santé et de la Recherche Médicale U396 Institut des Cordeliers, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC are the most potent APC (reviewed in Ref. 4), with the
unique ability to prime naive T cells (5). Tissular DC are
considered as immature and can be identified by their expression of HLA
class I and II molecules, CD1a, CD40, CD80 (B7.1), and CD86 (B7.2) but
not CD83. They capture and process Ag with high efficiency. When DC
receive inflammation signals mediated by chemokines
(macrophage-inflammatory protein 3
, macrophage-inflammatory protein
1, and RANTES) and cytokines (TNF-) or membrane ligands (CD40-L),
they migrate from tissues to peripheral lymph nodes. In the course of
their migration, they undergo maturation and are considered mature when
localized in lymph nodes. Mature DC express CD83 (6) and
have enhanced HLA class I, class II, CD80, and CD86 expression
(7). Immature DC can be generated in vitro from either
peripheral blood monocytes (8) using GM-CSF and IL-4 or
from CD34+ hemopoietic stem cells
(9) using GM-CSF and TNF-. Maturation of cultured
immature DC may be obtained by a 48-h incubation with TNF-,
bacterial LPS (10), or CD40-L (11). DC
differentiation and maturation can therefore be reproduced in vitro.
The success of Ag presentation by DC has led to them being considered
as promising tools for immunotherapy (12, 13).
Macrophages express HLA class I and HLA class II Ags as well as CD80 and CD86 accessory molecules (14). They are characterized by their high ability to phagocytose, which allows them to process and to present particulate Ags. However, macrophages are less effective than DC in Ag presentation to T lymphocytes (15, 16).
B lymphocytes are considered to be professional APC (17)
and express the requisite accessory molecules for T lymphocyte
activation (such as CD86, CD80, and CD40 molecules (18))
as well as HLA class II molecules. There is ample evidence for
HLA-DR-mediated signal transduction in B lymphocytes (reviewed in Ref.
19). The intracytoplasmic region of the HLA-DR ß-chain
is critical for the translocation of protein kinase C and ßII
(20). Consequences of these signals are either
proliferation and differentiation (21), cell-cell adhesion
(22), or cell death (23). Activated human B
lymphocytes are more susceptible to HLA-DR-mediated apoptosis than
resting cells (24, 25). The mechanism of HLA-DR-mediated
cell death has not been elucidated, although enhancement of sensitivity
to CD95/Fas (26) and expression of Fas-L (27)
has been described after HLA-DR cross-linking. Fas, in common with
other death receptors, initiates activation of cysteinyl
aspartate-specific proteinases (caspases) which are considered as the
principal executioners of Fas-induced apoptosis (28, 29).
Ag presentation needs TCR and CD4 interaction with HLA class II molecules but also activation of cells by costimulation molecules (30). Numerous mechanisms to control the T cell response have been described (anergy, apoptosis). Mechanisms controlling the APC response have not yet been elucidated. Since HLA-DR mediated more cell death in activated than in resting B cells, it has been postulated to play a role in the termination of the immune response (23). If this were the case, HLA-DR-mediated cell death could be also expected to occur in other APC. Tyrosine protein kinase activation via HLA-DR on DC has been reported (31); however, the question of apoptosis has not been addressed.
We have examined the role of HLA-DR-mediated signals throughout differentiation of primary professional APC. Hemopoietic progenitors, monocytes, macrophages, as well as immature and mature DC were examined. We have compared DC derived from both monocytes and CD34+ cells of the same individual to ensure that the results obtained were representative of DC regardless of their origin. We report HLA-DR-mediated apoptosis of mature differentiated APC which did not appear to depend on caspase activation. An in vitro model of APC differentiation and maturation allowed us to demonstrate that the apoptotic function of MHC class II is differentially regulated in professional APC subsets. Finally, these results strongly suggest an "autoregulation" of MHC class II-mediated Ag presentation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following mAbs were used in cell cultures: Agonistic
anti-CD95 mAb (CH11, IgM
) was purchased from Immunotech
(Marseille, France). Monomorphic anti-HLA-DR mAb (L243, D1.12),
anti-HLA-DR and -HLA-DP mAbs (L227) were purified from ascitic
fluid. The W6.32 mAb was used to study HLA class I-mediated apoptosis.
IgG1 and IgG2a isotype-matched controls were purchased from PharMingen
(San Diego, CA). All mAbs used for cell cultures were conditioned
without sodium azide.
GM-CSF, IL-4, stem cell factor (SCF), Flt3-L and TNF- were purchased
from Life Technologies (Rockville, MD). LPS from Escherichia
coli was purchased from Sigma (St. Louis, MO).
Caspase inhibitors Z-VAD-fmk (32) and Z-DEVD-fmk (33) were purchased from Calbiochem (La Jolla, CA). They were resuspended in DMSO and used at a final concentration of 250 µM.
Cell lines
Cell lines from different lineages were obtained from the American Tissue Culture Collection (Manassas, VA). Raji is a B cell line isolated from a Burkitt lymphoma (34). Jurkat is a T cell line isolated from an acute T cell leukemia (35). THP-1 is a monocytic cell line isolated from an acute monocytic leukemia (36). KG1 is a myeloid cell line isolated from acute myeloid leukemia (37). TF-1 (38) is a myeloid cell line isolated from erythroleukemia. KG1 and TF-1 express CD34 and HLA-DR Ags, whereas Raji and THP-1 express HLA-DR and Jurkat does not express either HLA-DR or CD34. All cell lines were cultured in RPMI supplemented with 10% FCS, 2 mM L-glutamine, and 1 mM pyruvate. TF-1 culture medium was supplemented with 300 U/ml GM-CSF.
Cells
DC and macrophages were derived from monocytes isolated from buffy coats of normal healthy donors. Cytapheresis products were collected at the end of the chemotherapy-induced aplasia from patients with nonmyelomonocytic malignancies (non-Hodgkin lymphoma or multiple myeloma) to have access to both CD34-derived and monocyte-derived DC from the same donor.
Cell purification
After separation of PBMC on Ficoll, cells were washed twice in HBSS (Life Technologies) and 10% FCS. They were resuspended at 3 x106 cells/ml and incubated in 6-well microplates (3 ml/well) for DC and macrophage cultures. After a 2-h incubation at 37°C in 5% CO2, adherent cells were composed of 84.5 ± 5.8% CD14+ cells when analyzed by flow cytometry. Nonadherent cells were removed for isolation of CD34+ cells.
Nonadherent cells were allowed to adhere for another 30 min in 45-cm2 flasks to remove remaining monocytes before isolation of CD34+ cells. Hemopoietic progenitors were positively selected using CD34-conjugated immunomagnetic beads (Dynabeads M-450 CD34; Dynal, Oslo, Norway) according to the manufacturer’s instructions. The final purity of CD34+ cells was 88.9% ± 5.7% as demonstrated by flow cytometry analysis.
Generation of DC and macrophages
Macrophages. Monocytes (adherent cells) were cultured for 7 days in IMDM (Life Technologies) and 10% FCS supplemented with 800 U/ml GM-CSF. Cultures were fed by replacing half of the medium at day 3.
Monocyte-derived DC.
Adherent cells were cultured in IMDM, 10% FCS supplemented with 800
U/ml GM-CSF, and 1000 U/ml IL-4. Half of the medium was replaced at
days 3, 5, and 7 by fresh medium with 800 U/ml GM-CSF and 500 U/ml
IL-4. At day 7, 100 U/ml TNF- was added to culture to provided
mature monocyte-derived DC.
Hemopoietic progenitor (CD34+ cells)-derived DC.
Isolated CD34+ cells were cultured in IMDM, 10%
FCS supplemented with 500 U/ml GM-CSF, 2.5 U/ml SCF, 10 U/ml Flt3-L,
and 200 U/ml TNF-. Cultures were fed by replacing half of the
culture medium by fresh medium at days 5, 9, and 14. At day 14, 100
ng/ml LPS was added to provide mature CD34-derived DC.
Phenotypic analysis of cells by flow cytometry
Before labeling, cells were incubated for 1 h in human AB serum, at 4°C, to avoid nonspecific mAb binding. Several mAbs were used for immunolabeling: FITC- or PE-conjugated mouse mAb against CD1a, CD14, CD34, and HLA-DR, and FITC-labeled isotype controls were purchased from Immunotech whereas mAbs against CD40, CD83, CD86, and PE-labeled isotype controls were purchased from PharMingen/San Diego, CA). After immunolabeling, cells were analyzed by flow cytometry using a Cytoron (Ortho Diagnostics, Raritan, NJ) equipped with an argon laser operating at 488 nm. Data were acquired with the Immunocount II software (Ortho Diagnostics).
Detection of HLA-DR-induced cell death
For studies of HLA-induced apoptosis, cells were plated in 1 ml of culture medium consisting of IMDM supplemented with 10% FCS. Cells were cultured at a density of 1 x 105 cells/well, in 24-well plates, in the presence or absence of mAb L243, D1.12, L227, W6.32, or the relevant isotype-matched control at different concentrations as specified in Results. Cultures were maintained in a humidified atmosphere with 5% CO2 at 37°C. In some experiments, to determine the role of caspases, cells were seeded at 37°C for 30 min with 250 µM Z-VAD-fmk, Z-DEVD-fmk, or DMSO before adding mAbs.
Samples were harvested after 20 h of culture. Flasks containing adherent cells (monocytes and macrophages) were maintained for 1 h in ice before scraping. Cells were stained with PE-labeled CD14 (for monocytes and macrophages) or CD1a (for DC), for 30 min at 4°C, and then incubated with FITC-labeled annexin V to determine apoptosis. Flow cytometry gating allowed us to select cells that exhibit CD14 or CD1a Ag and to analyze their binding of annexin V, which is a membrane marker of apoptotic cells (39).
We also analyzed apoptosis of mature monocyte-derived DC using propidium iodide (PI). PI binds to DNA and is actively excluded by live cells. Cell viability was determined by trypan blue exclusion.
Statistics
The comparison between variables was analyzed using the Student t test for comparisons of percentages of cell death.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The indicated markers were used to define the following subsets of APC.
Monocytes. Monocytes expressed HLA-DR molecules and a
low level of CD40 and CD86 molecules (Fig. 1
a). They did not express
CD80.
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b).
Immature monocyte-derived DC. DC differentiation was
induced by 7 days of culture with GM-CSF and IL-4, 83.1% ± 11.1 of
cells exhibited CD1a Ag. They also expressed HLA-DR, CD40, CD80, and
CD86 but not CD83 Ag (Fig. 1c), in agreement with previous
reports of the immature DC phenotype.
Mature monocyte-derived DC. After a 48-h incubation
with TNF-, monocyte-derived DC had up-regulated HLA-DR, CD80, and
CD86 Ag expression and also expressed CD83 (Fig. 1d), such
an expression of these Ags is characteristic of mature DC.
CD34+ hemopoietic progenitors. Peripheral
blood CD34+ cells do not express any of the
following Ags: CD40, CD80, CD86, and CD83 (Fig. 1e).
Immature CD34-derived DC. After 14 days of culture with
GM-CSF, TNF-, SCF, and Flt3-L, to induce DC differentiation, 44.7%
± 3.7 of cells expressed CD1a as well as HLA-DR and CD40 and a low
level of CD80 and CD86 but <15% of CD1a+ cells
expressed the CD83 Ag (Fig. 1f); such a phenotype is
characteristic of immature DC.
Mature CD34-derived DC. In response to a 48-h
incubation with LPS, CD34-derived DC displayed induction of CD83:
51.7% ± 15.2 of CD1a+ cells expressed this Ag
(Fig. 1g).
Macrophages, immature DC, and mature DC were also morphologically identified after May-Grünwald- Giemsa staining (data not shown).
Mature DC are susceptible to HLA-DR-mediated cell death in a dose-dependent manner and regardless of their origin
We examined apoptosis induction of monocyte-differentiated DC from
peripheral blood of healthy individuals using increasing doses (from
0.5 to 10 µg/ml) of isotypic control IgG1, D1-12, or anti-HLA
class I mAb W6.32. Cell death was detected using annexin V staining.
This methodology allow us to assess specific HLA-DR-mediated cell death
and to exclude the implication of Fc
receptors. As shown in Fig. 2, anti-HLA-DR mAb specifically
induces cell death of mature DC in a dose-dependent manner. Specific
apoptosis was not significantly increased by signaling via HLA class I
Ags (even when saturating levels, 10 µg/ml, of W6.32 were used).
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a). The cell death was
further corroborated by PI binding (Fig. 3b). Moreover,
apoptosis of cells was further established by counting the absolute
cell number detected after trypan blue staining. The absolute number of
DC decreased after stimulation via HLA-DR and the number of trypan blue
cells increased. PI or annexin V-positive cells of all samples exhibit
morphologic changes typical of apoptotic cells, including a low forward
scatter. Similar results (data not shown) were obtained with DC
differentiated from monocytes of patients who had undergone
chemotherapy or with DC differentiated from CD34+
cells of the same individuals. Identical results were obtained using
the L227 mAb. Taken together, these results demonstrate that mature DC
are susceptible to apoptosis via HLA-DR regardless of their origin.
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Having observed HLA-DR-mediated apoptosis of DC, we examined the
role of caspases in this pathway. Because of the limited number of
cells available, the approach that we have taken was to use
cell-permeable irreversible inhibitors of caspases. Z-VAD-fmk inhibits
a broad spectrum of IL-1-converting enzyme-like proteases
(32), whereas Z-DEVD-fmk is specific for caspase 3
(33). Because we did not observe any inhibition of
HLA-DR-mediated apoptosis in the presence of low concentrations of
Z-VAD-fmk or Z-DEVD-fmk (data not shown), in the experiments shown,
high concentrations were used (250 µM) to ensure that the absence of
inhibition was not due to the effect of dose. Whereas Fas-induced
apoptosis of Jurkat cells was dramatically inhibited by either peptide,
neither Z-VAD-fmk nor Z-DEVD-fmk altered HLA-DR apoptosis of mature
DC (Fig. 4).
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We then compared HLA-DR-mediated apoptosis of APC of the monocytic lineage. Positive and negative controls were provided by Raji B cells which underwent apoptosis in the presence of HLA-DR mAb, whereas viability of the HLA class II-negative Jurkat T cell line was unchanged.
Monocytes, macrophages, and monocyte-derived DC
We failed to detect significant apoptosis of monocytes in the
presence of HLA-DR mAbs. Since HLA-DR-mediated apoptosis of monocytes
has been described (40), we tested the monocytic cell line
THP-1, which expresses the same level of HLA-DR molecules as normal
monocytes. THP-1 like normal monocytes did not apoptose after
HLA-DR cross-linking (data not shown). However, after primary monocyte
differentiation to macrophages, sensitivity to HLA-DR-mediated cell
death was clear (Fig. 5): 17.0% ± 6.1
of annexin V after culturing in the presence of L243 mAb compared with
8.6% ± 2.0 culturing with an isotype control (n = 4,
p < 0.05).
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).
Finally, HLA-DR-mediated signaling led to death in mature
monocyte-derived DC (Fig. 5): 50.8% ± 17.0 of annexin V staining
cells using L243 mAb vs 11.52% ± 3.5 in the presence of an isotype
control (n = 4, p < 0.01).
CD34+ cells and CD34-derived DC
Primary CD34+ cells were resistant to
HLA-DR-mediated death (Fig. 5). Because of the high level of
spontaneous apoptosis in primary CD34+ cells, we
confirmed these data using two CD34+ cell lines,
KG1 and TF1, which do not undergo spontaneous apoptosis. Both of
these cell lines express levels of HLA-DR comparable to those of
CD34+ primary cells. In agreement with the
results from the primary CD34+ cells, neither
cell line was susceptible to HLA-DR-mediated apoptosis (data not
shown).
Similar to monocyte-derived DC, differentiation of
CD34+ cells to immature DC led to sensitivity to
HLA-DR-mediated cell death: 32.7% ± 8.0 of annexin V staining using
L243 mAb vs 13.2% ± 1.2 using an isotype control (n =
4, p < 0.01). The level of HLA-DR-mediated apoptosis
was therefore comparable in either CD34 or monocyte-derived DC
(Fig. 5).
Furthermore, maturation of CD34-derived DC with LPS significantly
increased their sensitivity to HLA-DR-mediated cell death: 50.7% ±
5.9 of apoptotic cells were detected vs 10.9% ± 2.5 using an isotype
control (n = 4, p < 0.001). The
difference between the apoptotic response induced via HLA-DR in either
immature or mature CD34-derived DC was significantly different:
p < 0.05 (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we differentiated DC from CD34+ hemopoietic progenitors and from monocytes of the same individual, therefore permitting valid comparison of DC of either origin. HLA-DR Ag expression was higher on monocyte-derived DC than on CD34-derived DC. Despite this phenotypic difference, DC differentiated from monocytes or CD34+ cells were remarkably similar with regard to their sensitivity to HLA-DR-mediated apoptosis and this remained the case even after maturation.
CD34+ cells and monocytes are resistant to HLA-DR-mediated apoptosis, whereas macrophages were sensitive and DC were even more sensitive and particularly after maturation. A correlation between the differentiation state of B cells and their ability to transmit HLA-DR-mediated signal has been described (24, 41). We show that, although macrophages and immature DC are fully differentiated cells, macrophages scarcely undergo apoptosis whereas immature DC do so clearly. We therefore propose that HLA-DR signaling for apoptosis correlates with the ability to present Ag rather than with simply the differentiation state of the cells. We have previously reported (3) that HLA-DR expression is 4.6-fold higher in immature DC than in monocytes and 1.5-fold higher in immature DC than in macrophages. HLA-DR-mediated death was most significant on populations that had acquired expression of the costimulatory molecules CD80 and CD86. Indeed, CD34+ cells do not express these two Ags; monocytes lack CD80 and express a low level of CD86. Macrophages express CD80 and a low level of CD86 and immature monocyte-derived DC like CD34-derived DC express a higher level of both these Ags, which are again up-regulated during DC maturation. Indeed, our data show that HLA-DR-mediated cell death correlates with the acquisition of requisite molecules for optimal Ag presentation. Moreover, it was demonstrated that macrophages are less effective than DC in inducing T cell responses (15, 16). Taken together, these data support the hypothesis that HLA-DR-mediated apoptosis is linked to Ag presentation capacity.
In activated B lymphocytes, it has been shown that HLA-DR-mediated cell death involves Fas/Fas-L interaction. However, a caspase-independent mechanism of HLA-DR-mediated apoptosis has been recently reported in mature normal and tumoral B cells (42). We have used cell-permeable and irreversible caspase inhibitors to establish that HLA-DR apoptosis of DC occurs in a caspase-independent manner. Nonetheless, it is clear that these experiments only allow us to exclude caspases specifically inhibited by either Z-VAD-fmk or Z-DEVD-fmk. There is increasing evidence that apoptosis can occur in a caspase-independent manner. Overexpression of the PML (43) gene product triggers apoptosis in the absence of caspase 3 activation and caspase inhibitors are inefficient in inhibiting this apoptotic pathway (44). In the same way, NO-induced cell death is not inhibited by YVAD-mca and DEVD-mca caspase inhibitors (45). However, overexpression of bax induced certain, but not all, features of apoptosis even in the presence of caspases inhibitors (46). A recently described mitochondrial apoptosis-inducing factor (47) is contained inside the mitochondrial intermembrane space and could be released into the cytosol and nucleus upon pore opening by increasing intracellular Ca2+ concentration. The apoptotic activity of apoptosis-inducing factor is maintained in the presence of Z-VAD-fmk caspase inhibitor. We are currently examining the mechanisms of HLA-DR-mediated apoptosis in APC of the DC/monocytic cell lineage.
The importance of this study is not only in the revelation of HLA-DR signals leading to apoptosis of the APC but also the determination of the hierarchy of susceptibility which reflects the hierarchy of Ag presentation capacity. These data provide strong support for the notion that HLA-DR-induced apoptosis reflects a mechanism of down-regulation of the immune response. Further support from this notion came from the following observations of disappearance, in lymph node, of DC after interaction with Ag-specific T cells (48), signal transduction in DC after T cell contact (49), and the induction of apoptosis of DC after an Ag-specific T cell interaction (50).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nuala Mooney, Laboratoire d’Immunogénétique Humaine, Institut Biomédical des Cordeliers, 15 rue de l’école de médecine/Bat A, 75006 Paris, France.
3 Abbreviations used in this paper: DC, dendritic cell; SCF, stem cell factor; L, ligand; PI, propidium iodide.
Received for publication July 12, 1999. Accepted for publication December 20, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Exp. Med. 179:1109. cooperate in the generation of dendritic Langerhans cells. Nature 360:258.[Medline]
and PKCß II isoforms is abrogated following truncation of DRß cytoplasmic domains. J. Immunol. 159:3792.[Abstract]
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A. M. Woltman, J. W. de Fijter, S. W. A. Kamerling, S. W. van der Kooij, L. C. Paul, M. R. Daha, and C. van Kooten Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages Blood, July 1, 2001; 98(1): 174 - 180. [Abstract] [Full Text] [PDF]
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K. D. Kim, Y.-K. Choe, I. S. Choe, and J.-S. Lim Inhibition of glucocorticoid-mediated, caspase-independent dendritic cell death by CD40 activation J. Leukoc. Biol., March 1, 2001; 69(3): 426 - 434. [Abstract] [Full Text]
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