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IMMUNOBIOLOGY
From the Laboratoire d'Immunologie des Tumeurs,
Laboratoire de Cytogénétique, and Département
d'Hématologie of the Institut Paoli-Calmettes, Université
de la Méditerranée; Immunotech, Beckman-Coulter;
Laboratoire de Virologie, Hôpital La Timone; and Institut
National de la Santé et de la Recherche Médicale (INSERM)
U119, Marseille, France; and Schering-Plough, Laboratory for
Immunological Research, Dardilly, France.
Dendritic cells (DCs) are responsible for the initiation of immune
responses. Two distinct subsets of blood DCs have been characterized
thus far. Myeloid DCs (MDCs) and plasmacytoid monocytes (PDCs) were
shown to be able to promote polarization of naive T cells. This study
shows a dramatic quantitative imbalance in both circulating blood DC
subsets in 37 patients with acute myeloid leukemias. Eleven patients
(30%) displayed a normal quantitative profile (MDC mean,
0.37% ± 0.21%; range, 0.01% to 0.78%; PDC mean, 0.21% ± 0.24%; range, 0.04% to 0.62%), whereas 22 (59%) showed a tremendous expansion of MDCs (9 patients: mean, 16.76% ± 14.03%; range, 1.36% to 41%), PDCs (4 patients: mean, 7.28% ± 6.84%;
range, 1% to 14%), or both subsets (9 patients: MDC mean,
10.86% ± 12.36%; range, 1.02% to 37.1%; PDC mean,
4.25% ± 3.78%; range, 1.14% to 13.04%). Finally, in 4 patients
(11%), no DC subsets were detectable. Both MDC and PDC subsets
exhibited the original leukemic chromosomal abnormality. Ex vivo,
leukemic PDCs, but not leukemic MDCs, had impaired capacity for
maturation and decreased allostimulatory activity. Also, leukemic PDCs
were altered in their ability to secrete interferon- Dendritic cells (DCs) are bone marrow-derived
leukocytes that are responsible for the initiation of immune responses
and exert a sentinel-like function.1 DCs are
phenotypically and functionally heterogeneous in vivo. In humans, 2 distinct subsets of blood DCs have been characterized based on the
differential expression of CD11c.2 Myeloid DCs (MDCs) and
plasmacytoid monocytes (PDCs) were shown to be able to promote
polarization of naive T cells into Th1 or Th2.3-6 Th1 and
Th2 cells are cross-regulatory in vitro. The balance of these cells in
vivo determines the character of cell-mediated immune and inflammatory
responses.7 Furthermore, PDCs are crucial effectors in
antiviral innate immunity. They can also induce Th1 development through
secretion of type 1 interferon (IFN).4,5 Thus, blood
circulating DCs may play a key role in promoting antitumor immunity.
Tumor-associated DCs have been shown to have a low allostimulatory
capacity, particularly if isolated from progressing metastatic lesions,
as in malignant melanoma.8 DC numbers were shown to be
increased in certain hematologic diseases, such as Hodgkin disease,9 or decreased in others, such as myelomonocytic
leukemia,10 but the significance of this is unknown. We
and others reported previously that myeloid leukemic cells were able to
differentiate into mature DCs in vitro.11-16
Because the relation between the various DC differentiation pathways
and the hematopoietic progenitors remains unclear, the development of
blood circulating DCs in vivo might be affected by leukemic cell
proliferation. In this study, we investigated whether circulating DCs
could be detected in the blood of patients with acute myeloid leukemia
(AML). We show here a dramatic quantitative imbalance in blood DC
subsets among the majority of 37 patients with myeloid leukemias. Both
MDC and PDC subsets were found to exhibit the original leukemic
chromosomal abnormality. Leukemic PDCs have impaired capacity for
maturation, decreased allostimulatory activity, and alteration in their
ability to secrete IFN- Patient samples
Cell lines
Blood DC detection and sorting Blood DCs were identified by 3-color staining performed on PBMCs using the following monoclonal antibodies: ZM3.8-PC5 (mAb against ILT3, an immunoglobulinlike transcript recently used to isolate DCs from the blood, mouse IgG1),17 BU15-phycoerythrin (PE) (mAb against CD11c), and fluorescein isothiocyanate (FITC)-labeled mAbs against lineage markers CD14, CD16, CD19, and CD56 (Beckman-Coulter, Marseille, France). Cells that did not label with these lineage markers were designated as lin . The purity of each DC subpopulation
after cell sorting was always greater than 98% and was assessed by
fluorescence-activated cell sorting (FACS) before subsequent
fluorescence in situ hybridization (FISH) and functional
experiments. The following mAbs were used for flow cytometry
studies: HLA-DR, CD13, CD33, CD45RA, CD45RO, CD4, CD5, CD116, CD1a, and
CD83 (Beckman-Coulter); and CD80, CD86, CD123, and CD40 (Pharmingen,
San Diego, CA). Stained cells were analyzed on a FACSCalibur cytometer
using Cellquest software (Becton Dickinson, San Jose, CA). DCs were
sorted on a FACSVantage cytometer (Becton Dickinson).
FISH analysis Interphase FISH was performed as described previously on cytospin preparations with sorted MDCs and PDCs from 4 patients selected for detection of their cytogenetic abnormality.18 For detection of trisomy 8 (unique patient number 156 [UPN156] and UPN79) and monosomy 7 (UPN223), metaphases were analyzed with a specific probe for chromosome 8 (D8Z2 probe) or chromosome 7 (D7Z1 probe), both purchased from Oncor (Gaithersburg, MD). For the detection of translocations associated with the q23 region of chromosome 11 (UPN109), LSI MLL dual-color DNA probe (Vysis, Downers Grove, IL) was used. At least 200 nuclei were examined under fluorescence microscopy by 2 independent observers.Confocal microscopy Cells were adhered to polylysine-coated glass slides for 30 minutes at room temperature, fixed in 4% paraformaldehyde, and permeabilized in 0.1% Triton in phosphate-buffered saline. Cells were then labeled with different primary mAbs and revealed by species-specific Alexa 488, tetramethylrhodamine isothiocyanate (TRITC; Molecular Probes, Eugene, OR), or cyanin 5-labeled secondary antibodies (Jackson Immunoresearch, West Baltimore Pike, PA). DC-LAMP mAb was kindly provided by Serge Lebecque (Schering-Plough, Laboratory for Immunological Research).19 Slides were then mounted using fluorescent mounting medium (Dako, Trappes, France). Confocal analysis was performed with a TCS NT microscope equipped with argon and krypton ion lasers and a X100 1.3NA PL fluotar objective (Leica Microsystem, Heidelberg, Germany).Reverse transcriptase-polymerase chain reaction analysis Expression of pre-T transcript on freshly sorted MDCs and
PDCs was analyzed as described previously.20 Briefly,
total cellular RNA was extracted from the FACS-sorted cells using
TRIzol reagent (Gibco BRL, Cergy-Pontoise, France). First-strand cDNAs
were prepared using oligo(dT) primers and murine Moloney leukemia
virus reverse transcriptase (RT; Gibco BRL). Polymerase
chain reaction (PCR) amplification was performed for 35 cycles (1 minute at 94°C, 1 minute at 55°C, and 2 minutes at 72°C) with Taq
DNA polymerase (Gibco BRL). Oligonucleotide primers for pre-Ta
were 5'-GGCACACCCTTTCCTTCTCTG-3' and 5'-GCAGGTCCTGGCTGTAGAAGC-3' for
sense and antisense primers, respectively.
Functional analysis To evaluate T-cell proliferation capacity, we sorted ILT3+CD11c (PDCs) and
ILT3+CD11c+ (MDCs) from peripheral blood from
healthy volunteers or leukemic patients and cultured them in 48-well
culture plates in RPMI 1640 medium containing 10% fetal calf serum
(BioWhittaker, Verviers, Belgium) in the presence of 100 ng/mL
granulocyte macrophage colony-stimulating factor (GM-CSF; kindly
provided by Novartis, Berne, Switzerland) and 20 ng/mL interleukin-4
(IL-4) (kindly provided by Schering-Plough Research Institute,
Kenilworth, NJ) for MDCs or 10 ng/mL IL-3 (Genzyme, Cergy St
Christophe, France) for PDCs. Cells were stimulated by adding 75 Gy-irradiated CD40L-transfected cells (1 × 104/well).
Freshly isolated and 3-day-cultured DCs were cocultured with
1 × 105 allogeneic naive CD4+ T cells in
96-well flat-bottom plates for 6 days. Proliferation of T cells was
monitored by measuring methyl-[3H]thymidine (Amersham,
Little Chalfont, United Kingdom) incorporation during the last
12 hours of culture on a gas-phase  counter (Matrix 9600; Packard,
Downers Grove, IL). Naive CD4+ T cells were
prepared from adult donor PBMCs negatively depleted of CD8, CD14, CD19,
CD56, and CD45RO+ cells using goat anti-mouse Ig-coated
magnetic beads (Beckman-Coulter). Fully 98% of the resulting cells
were CD4+CD45RA+ as controlled by FACS
analysis. To determine cytokine production, we cultured freshly sorted
DCs in 96-well flat-bottom plates at a concentration of
2 × 104 cells/well and stimulated them with either
CD40L-transfected cells (2000 cells/well) or 106 PFU/mL
herpes simplex virus 1 (HSV). Supernatants were collected after 24, 48, and 72 hours and tested for their cytokine contents. IFN- levels
were measured by enzyme-linked immunosorbent assay (Beckman-Coulter).
Imbalance of blood DC subsets in myeloid leukemia patients Circulating blood DC subsets from 37 leukemic patients were analyzed at diagnosis and before treatment by flow cytometry after staining with lineage markers (CD14, CD16, CD19, and CD56), CD11c, and ILT3, an immunoglobulinlike transcript recently used to isolate DCs from the blood.6 In healthy individuals, 2 distinct populations of lin/ILT3+ cells were observed
with respect to the expression of CD11c, with the phenotypes of
lin/CD11c/ILT3+ (PDCs) and
lin/CD11c+/ILT3+ (MDCs) (Figure
1). The MDC and PDC subsets represented,
respectively, 0.26% ± 0.23% (range, 0.01% to 0.8%) and
0.24% ± 0.18% (range, 0.01% to 0.7%) of PBMCs in the different
healthy volunteers (HVs) that we analyzed (n = 15) and are in
accordance with those already published21 (Table
1). Leukemic samples representing the
different subgroups of the FAB classification (3 M1, 2 M2, 3 M3, 8 M4,
18 M5, 1 M6, and 2 M7) were analyzed and revealed an important
quantitative imbalance in the proportions of circulating MDC and PDC
subsets, as exemplified by the 2 samples shown for patients UPN109 and UPN223 (Figure 1). Eleven patients (30%, group I) displayed a normal
quantitative profile (MDC mean, 0.37% ± 0.21%; range, 0.01% to
0.78%; PDC mean, 0.21% ± 0.24%; range, 0.04% to 0.62%), whereas 22 (59%, group II) showed an expansion of MDCs (9 patients: mean, 16.76% ± 14.03%; range, 1.36% to 41%), PDCs (4 patients: mean, 7.28% ± 6.84%; range, 1% to 14%), or both subsets (9 patients: MDC mean, 10.86% ± 12.36%; range, 1.02% to 37.1%; PDC mean,
4.25% ± 3.78%; range, 1.14% to 13.04%). Finally, in 4 patients
(11%, group III), no DC subsets were detectable (Table 1). Hereafter, all immunophenotypic and functional assays were performed in different patients taken in both groups I and II.
Phenotypic comparisons of freshly isolated MDCs and PDCs from HVs and
from patients were performed, indicating their similarity to the 2 previously described subsets of precursor DCs, one lacking and one
expressing CD11c.6,22 MDC populations isolated from patients expressed the myeloid markers CD11c, CD13, and CD33, as well
as CD5, CD45RO, and the GM-CSFR
Morphology of the 2 blood DC subsets was assessed after culture in the
presence of GM-CSF, IL-4, and CD40L for MDCs and IL-3 and CD40L for
PDCs. MDCs from both HVs and patients showed large clusters with many
long and fine dendrites (Figure 3 and
data not shown), whereas freshly isolated PDCs displayed a
characteristic lymphoid or plasma cell-like shape with no or fewer
polarized dendrites, resembling the previously described plasmacytoid T cells (Figure 3E).2 Confocal microscopy of cultured MDCs
isolated from blood of patients revealed their typical DC morphology
(Figure 3).
Leukemic origin of circulating blood DC subsets The leukemic origin of freshly isolated MDC and PDC populations from patients with AML was investigated by examining the presence of cytogenetic abnormalities by FISH experiments. MDCs and PDCs from 4 patients taken in both groups I and II (UPN79, UPN109, UPN156, and UPN223) displaying cytogenetic abnormalities on their leukemic blasts at diagnosis were analyzed. All freshly sorted MDCs and PDCs from these patients, with or without quantitative expansion of DC subsets, exhibited the initial cytogenetic abnormalities. Examples of MDCs from one AML patient with trisomy 8 at diagnosis (UPN156) are depicted in Figure 4. A red hybridization signal on all of the analyzed nuclei showed the presence of trisomy 8 on sorted MDCs. These results demonstrated the leukemic status of blood circulating DC subsets in patients with myeloid leukemia.
Impaired in vitro maturation of PDCs isolated from patients Freshly sorted MDCs and PDCs isolated either from HVs or from leukemic patients were cultured for 3 days in the presence of GM-CSF and IL-4 for MDCs and IL-3 for PDCs. We examined their capacity to undergo maturation after either simultaneous in vitro culture with appropriate cytokines and CD40L for 3 days or 3 days with cytokines followed by 2 days of stimulation by CD40L. Phenotypic analysis indicated that both subsets isolated from HVs acquired the expression of CD83 and expressed the costimulatory molecules CD80 and CD86. The expression of HLA-DR was up-regulated, especially on the MDC subset (Figure 5A,C). In leukemic patients, the MDC subset could acquire CD83 and the costimulatory molecules CD80 and CD86 (Figure 5B). Acquisition of CD83 and distribution of HLA-DR molecules on leukemic MDCs were further confirmed by confocal microscopy staining (Figure 3B,C). Furthermore, confocal staining of MDCs indicated that they expressed DC-LAMP after maturation in culture (Figure 3D), which is a newly described DC-specific lysosomal marker specifically induced in maturing DCs.19 In contrast, PDCs from leukemic patients never acquired CD83 or costimulatory molecules, even after prolonged culture or with the addition of tumor necrosis factor- (TNF-; Figure 5D and data not shown). These results
strikingly indicate that PDCs isolated from leukemic patients display
altered capacities for maturation as compared with their healthy
counterparts.
Functional properties of MDCs and PDCs from leukemic patients MDCs and PDCs were assessed for their ability to stimulate naive CD4+ T cells in an allogeneic mixed lymphocyte reaction. Freshly isolated and 3-day-cultured MDCs obtained either from HVs or leukemic patients could efficiently stimulate the proliferation of naive CD4+ T cells (Figure 6A and data not shown). As described previously,2,26 freshly isolated PDCs from HVs induced weak, if any, proliferation of naive allogeneic T cells (Figure 6B). After culture in the presence of IL-3 and CD40L, there was an increase in the allostimulatory activity of PDCs from HVs (Figure 6B). In marked contrast, even after culture, leukemic PDCs were inefficient to induce proliferative responses by naive T cells (Figure 6A,B).
PDCs proved recently to be the main producers of type I IFN-
Our results show that the 2 circulating DC subsets can be
identified in the blood of patients with AML. No specific marker is
currently available for positive identification of circulating DCs. A
method based on a lin Our results among 37 AML patients show an important quantitative imbalance for MDCs and PDCs. The clinical relevance of increased blood DC numbers is not yet clear. Recently, it has been proposed that PDCs might be responsible for maintaining peripheral T-cell tolerance to self-antigens.3 The balance of these cells in vivo influences the character of cell-mediated immune and inflammatory responses and may interfere in the mechanisms regulating antitumor immunity versus tolerance. FISH analysis confirmed that MDCs and PDCs had the same cytogenetic abnormalities expressed by freshly isolated leukemic cells. Therefore, DCs in leukemic patients may be part of the malignant clone, or "dendritopoiesis" is affected by the leukemic process. The latter does not exclude that normal MDC and PDC subsets without cytogenetic abnormalities might circulate in the blood of these leukemic patients. Because of the quantitative predominance of leukemic MDC and PDC subsets, such normal subsets could not be detected. Furthermore, at present, the different differentiation pathways of DCs are not clearly established. At this stage, though MDC and PDC development appears to be affected by the leukemic process, we cannot confirm whether circulating DCs in leukemic patients originate exclusively from the leukemic clone or from another stem cell with expression of leukemic cytogenetic markers. The recognized characteristics of DCs include the ability to present antigens and to stimulate specific T-cell responses. Leukemic MDCs and PDCs might express at least some leukemia-related proteins associated with the cytogenetic abnormality, but this does not necessarily mean that they will be efficiently presented to T cells. The crucial role of costimulatory molecules in the generation of an antileukemic response has been shown in murine leukemia models.32,33 In the current study, we have demonstrated that PDCs from leukemic patients could not acquire CD80 and CD86. The same held true for HLA-DR, which was weakly expressed on leukemic PDCs after culture. On the other hand, MDCs could achieve increased expression of the costimulatory molecules, which correlated with their capacity to induce naive CD4+ T-cell proliferation. This maturation process was associated with the expression of CD1a and CD83. These properties and markers helped to define the maturation pattern of these cells toward the DC lineage.30 Our results established a clear difference in the function of leukemic circulating DCs compared with their normal counterparts. Stimulation through the CD40 pathway failed to enhance the allostimulatory activity of PDCs from leukemic patients, which is compatible with the absence or low expression of HLA-DR and costimulatory molecules. It has been shown recently that PDCs produce large amounts of type I
IFN after microbial challenge.4-6,27 The in vivo effects of type I IFN are associated with promoting an antiviral state, including a broad spectrum of cellular targets.34 Type I
IFN plays an essential role in antiviral immunity and is widely used to
treat viral hepatitis and various types of malignancies, especially chronic myeloid leukemia.35 These effects appear to be due
to direct inhibition of viral replication in infected cells and to the
pleiotropic immunomodulating activity of type I IFN.35
Type I IFN may act by enhancing the cytotoxic activity of natural
killer cells and macrophages,35 by inducing T-cell
activation,36 or by maintaining the survival of activated
T cells.37 It has also been shown that IFN- In summary, in AML patients, both circulating DC subsets exhibit quantitative abnormalities and exhibit leukemic cytogenetic features. The leukemic process, through interference with the DC system, appears to contribute to creating a state of profound immune suppression in AML patients. Although leukemic, MDCs retain the ability to differentiate, whereas PDCs show altered immunogenicity. The latter suggests that PDCs may play a key role in AML and other cancers where the immune system appears to be suppressed or otherwise "tolerized" to the tumors. Further studies are warranted to investigate the clinical relevance of altered circulating blood DC numbers in leukemic patients and the potential role of PDCs in the induction of tolerance to leukemic cells.
We thank N. Bendriss-Vermare (Schering-Plough, Laboratory for Immunological Research, Dardilly) for helpful discussions and L. Leserman (Centre d'Immunologie de Marseille Luminy), D. Blaise, D. Maraninchi (Institut Paoli-Calmettes), and C. Mawas (INSERM, Marseille) for their critical reading of the manuscript. We also thank R. Galindeau for assistance in cell sorting and S. Just-Landi and N. Baratier for excellent technical assistance.
Submitted February 21, 2001; accepted August 10, 2001.
Supported by grant "Mitjavile" from the Academie Nationale de Medecine, Paris, France (to M.M.).
D.J. has declared a financial interest in Beckman-Coulter, whose product was studied in the present work. D.J. was employed by Beckman-Coulter (Marseille) at the time of this study.
D.O. and B.G. contributed equally to this study.
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: Béatrice Gaugler, Immunologie des Tumeurs, Institut Paoli-Calmettes, 232 Bd Ste Marguerite, 13273 Marseille Cedex 09, France; e-mail: gauglerb{at}marseille.fnclcc.fr.
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© 2001 by The American Society of Hematology.
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H. Hashizume, T. Horibe, H. Yagi, N. Seo, and M. Takigawa Compartmental Imbalance and Aberrant Immune Function of Blood CD123+ (Plasmacytoid) and CD11c+ (Myeloid) Dendritic Cells in Atopic Dermatitis J. Immunol., February 15, 2005; 174(4): 2396 - 2403. [Abstract] [Full Text] [PDF]
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F. Garnache-Ottou, L. Chaperot, S. Biichle, C. Ferrand, J.-P. Remy-Martin, E. Deconinck, P. D. de Tailly, B. Bulabois, J. Poulet, E. Kuhlein, et al. Expression of the myeloid-associated marker CD33 is not an exclusive factor for leukemic plasmacytoid dendritic cells Blood, February 1, 2005; 105(3): 1256 - 1264. [Abstract] [Full Text] [PDF]
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M. R. Comeau, A.-R. Van der Vuurst de Vries, C. R. Maliszewski, and L. Galibert CD123bright Plasmacytoid Predendritic Cells: Progenitors Undergoing Cell Fate Conversion? J. Immunol., July 1, 2002; 169(1): 75 - 83. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
) or patient UPN109
(
), or 3-day-cultured PDCs from healthy donor (
) or patient
UPN109 (
), were cocultured with 105 CD4+
naive T cells for 6 days. CD14+ monocytes (purified by
magnetic separation using CD14 microbeads; Myltenyi Biotec
GmbH, Bergisch Gladbach, Germany) from healthy donor (
) were
prepared and used as control stimulators. Representative data of 3 experiments are shown.
-secreting
CD4+ T cells with cytolytic activity.
), myeloid CD11c(+), and mature interdigitating dendritic cells.
J Clin Invest.
2001;107:835-844