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Regular Articles |
From the Departments of Obstetrics and Gynecology,*
Pediatrics,
and
Dermatology,
the University of
Würzburg, Würzburg, Germany
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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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The human decidua is invested with a significant (up to 75% of all major histocompatibility complex (MHC) class I+ cells are CD45+) and diverse population of leukocytes.2,3 Nearly one fifth of decidual leukocytes are positive for MHC class II and are thought to be mostly macrophages.4 The most abundant cell type of decidua are uterine-specific natural killer cells, the large granular lymphocytes (LGLs),5 whereas T cells are sparse and B cells are virtually absent.3,5 The decidual leukocyte population has been a center of interest for the understanding of the balance between maternal control of the extent of invasion of FTBs in the uterine wall2-6 as well as acceptance of the allogeneic fetus in successful pregnancy.1 Although it is not known how this balance is achieved, it is possible that the antigenic handling and processing in the decidua may differ from that of other regions of the body.
Antigen presenting cells (APCs) are specifically equipped to initiate and maintain immune responses.7 Among these APCs, bone marrow-derived DCs are the most potent activators of naive T-lymphocyte responses.8,9 DCs seed surface areas, such as the epidermal layer of the skin and the mucosal membranes as well as the interstitial spaces of solid organs,10,11 playing a sentinel function for the immune system. In vivo, DCs exhibit a distinct shape, described as veiled or dendritic,12 express high levels of MHC class II products and are able to migrate selectively through tissues.10,13 After isolation and a period of cell culture, DCs undergo specific functional changes in migratory properties and co-stimulatory features which may mimic the in vivo maturation process. Cultivated DCs exhibit membrane processes on the surface which bend, retract, and re-extend in a nonpolarized fashion14 and are the major stimulators of autologous and allogeneic mixed leukocyte reactions (MLRs).9
Although there is considerable interest in DCs, working with these cells is hampered because of their low frequency in blood15 and tissue.16 Additionally, the lack of an antibody specific for the early stages of DCs makes identification and isolation of fresh DCs difficult. In vivo, a proportion of mature DCs may be stained in tissue sections using either the CD83 or CMFR-44 monoclonal antibodies.17-19 DCs may be conveniently enriched after 1 to 2 days culture from blood or tissue suspensions as a low-density fraction.14,20,21 Using either direct selection for MHC class II-positive cells or depletion of contaminating lineage marker-positive cells, DCs have been successfully isolated from many tissues including blood, lymph nodes, skin, and lung.10,13
Recent studies have pointed to a role for DCs in the induction of peripheral tolerance.22,23 DCs are thus of outstanding interest as immune cells which may have the capacity to act in two roles: as potent APCs and also in the induction of peripheral tolerance. Therefore, DCs could be suitable candidates that mediate the balance of maternal defensive immune responses to foreign antigens but also tolerance to the conceptus in the human decidua.
The data presented here are intended to be the initiation for further studies of DCs in human early pregnancy decidua. To our knowledge, this is the first demonstration of CD83+ dendritic-like cells in human decidua, which show morphological, phenotypic, and functional characteristics of immunostimulatory mature DCs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All investigations were approved by the Ethics Committee of the Medical Faculty of the University of Würzburg, Germany.
Decidual tissue (decidua basalis and parietalis) was obtained from 21 healthy women undergoing legal therapeutic abortion of an intact, normally progressing pregnancy with documented fetal heart activity at 6 to 9 weeks of gestation after the last menstrual period. All specimens contained embryonic components as verified by macroscopic and histological examination. Decidual tissue was taken from each specimen to be snap-frozen in liquid nitrogen for histological examination and immunohistochemical staining. The remainder was kept for no more than 30 minutes in phosphate-buffered saline (PBS) before subsequent cell isolation.
In one case, a hysterectomy sample was obtained of a pregnant uterus at the10th week (last menstrual period) of gestation. The hysterectomy was performed because of cervical cancer in situ (CIN 3) with no involvement of the uterus. Tissue sections through placental and uterine tissue were snap-frozen for a immunohistochemical staining procedure. Ten samples of uterus with endometrium in the secretory phase were obtained after routine hysterectomy because of uterus myomatosus.
Immunohistochemistry
The antibodies applied in this study are listed in Table 1
.
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To evaluate the average density value of DCs in human first pregnancy decidua, CD83+ and CD1a+ cells were counted at 250-fold magnification in 150 single fields of 0.13 mm2 (=20 mm2) for each of two sections per patient by two independent observers. Fields were randomly selected over the entire cryostatic section and completely filled with nonnecrotic cells. Decidua basalis samples with more than five invading FTBs per 25x objective field generally showed too many necrotic cells and thus were excluded from this study. Cells <0.2 mm distant to glandular epithelium were designated as "near to gland" and cells associated with more than 10 lymphocytes as "clustered."
Single Cell Isolation
For isolation of decidual cells, specimens were dissected free of products of conception and washed twice in PBS. The total decidual tissue (4 to 10 g) was then minced into fragments of ~1 mm3 and digested for 20 minutes at 37°C under slight agitation in PBS with 200 U/ml hyaluronidase (Sigma), 1 mg/ml collagenase type IV (Seromed, Berlin, Germany), 0.2 mg/ml DNase I (2500 Kunitz U/mg; Sigma) and 1 mg/ml bovine serum albumin/fraction V (Sigma). The cell suspension obtained was filtered through sterile stainless steel 50-µm wire mesh and washed once in PBS. The mononuclear cell population was then separated by centrifugation over a Histopaque–1077 density gradient (Sigma). For positive selection of CD83+ cells, the mononuclear cell fraction obtained was incubated (5 x 106 cells/ml) in RPMI 1640 medium supplemented with 10% inactivated fetal calf serum and 50 µg/ml gentamicin (R10; all supplied by Seromed) in a tissue-culture grade Petri dish at 37°C and 5% CO2 for 16 hours to allow macrophages, fibroblasts, and endothelial cells to adhere to the flask. Nonadherent cells were then collected and resuspended in PBS. The cells were labeled with CD83 (clone: HB15a, 2 µg/106 cells in PBS supplemented with 1.6% (w/v) human immunoglobulin; Beriglobin, Centeon, Marburg, Germany) in a total volume of 100 µl for 30 minutes at 4°C, washed once, incubated with bead-conjugated goat-anti-mouse antibody (Miltenyi, Bergisch Gladbach, Germany) in PBS supplemented with 1.6% (w/v) immunoglobulin for 20 minutes at 4°C and separated in a positive-selection column in a magnetic assisted cell sorting (MACS) separator (Vario-MACS, Miltenyi).
The positive CD83-enriched fraction containing decidual DCs was analyzed for the content of CD83+ and HLA-DR+ cells by flow cytometry and used for subsequent analysis in a primary MLR and for preparation of cytospin specimens.
Cytocentrifuge Preparations
For cytospin samples, aliquots of 3 x 104 of the isolated decidual cells, enriched for CD83+ cells, were suspended in 100 µl of PBS and cytocentrifuged onto 3-amino-propyltriethoxy-silane-treated slides. They were fixed in acetone for 10 minutes, rehydrated in TBS, and incubated with a goat-anti-mouse Fab fragment to block the attached selection antibodies. Then the slides were incubated with the monoclonal antibody (HLA-DR, CD83, CD1a) at the appropriate dilution. Bound antibodies were detected using the alkaline phosphatase anti-alkaline phosphatase method as described elsewhere,24 and cells were counterstained with Mayer’s hematoxylin. Detection reactions without primary antibody and with isotype antibodies served as negative controls.
Flow Cytometry
Nonadherent cells after overnight culture and cells isolated by CD83+ selection were analyzed for cell-surface expression of a variety of leukocyte markers by fluorescence-activated cell sorting (FACS) analysis. Flow cytometry was performed with primary antibodies labeled with R-phycoerythrin (CD83) and fluorescein isothiocyanate (HLA-DR, CD45, CD1a, CD40, and CD14) or isotype control (mixture of mouse IgG1, IgG2a, IgG2b) antibodies. Aliquots of 2 x to 5 x 105 isolated cells were resuspended in 80 µl of PBS supplemented with 10% human immunoglobulin. Fluorochrome labeled antibodies (10 µl each) were added to the cell suspension and the preparation then incubated for 30 minutes at 4°C. Cell suspensions were washed once, resuspended in 200 µl of PBS, and then analyzed in a FACScan flow cytometer (Becton-Dickinson, Heidelberg, Germany). A total of 20,000 cells per sample were evaluated for specific staining. Results were analyzed using the WinMDI-Program (Version 2.8, 227 Joseph Trotter, The Scripps Research Institute, La Jolla, CA), setting the threshold at 0.5 and smoothing at 1.0 for the contour plots shown.
Motility and Morphology of Isolated DCs
To determine the morphology and motility of isolated cells, 1 x 105 cells/well per sample were seeded in a 96-well flat-bottom tissue culture plate in 100 µl of R10-medium per well. Morphology and motility were monitored daily for 7 days with an inverted microscope (Leica, Bensheim, Germany) with a video camera and documented for 3 minutes per day. One picture per 30 seconds was taken on an attached camera.
Primary MLRs
For control purposes, DCs were generated from blood monocytes
after standard procedures.25
In brief, peripheral blood
mononuclear cells derived from buffy coats of healthy volunteer donors
were prepared by isolation over a Histopaque–1077 density gradient,
resuspended in R10 and incubated at 5 x 106
cells/ml in a tissue-grade Petri dish to allow monocytes to adhere to
the bottom. The nonadherent cells were removed after 1 hour. The
adherent fraction was then cultured in R10 supplemented with GM-CSF
(1000 U/ml) and IL-4 (800 U/ml) for 7 days. One half the volume of
medium was replaced with fresh R10/GM-CSF/IL-4 at days 3 and 5, and at
day 7 one half of the volume of medium was replaced by fresh R10
supplemented with IL-1ß (1000 U/ml), TNF-
(1000 U/ml), IL-6 (1000
U/ml), and PGE2 (10-8
mol/L). At day 10 of culture, nonadherent cells with typical appearance
of DCs were collected, resuspended in 90% fetal calf serum/10% DMSO,
and aliquots stored in liquid nitrogen. Comparison of fresh and thawed
DCs showed no difference in their capacity as stimulator cells in the
MLRs.
For the MLRs, graded doses of decidual or blood monocyte DCs were cultured with 105 allogeneic T lymphocytes (prepared by 0.8% NH4Cl lysis of neuraminidase-treated sheep red blood cell rosettes of peripheral blood mononuclear cells) in a final volume of 200 µl of R10 in round-bottom 96-well plates (Falcon/Becton Dickinson, Franklin Lakes, NJ). For the MLR graphs, decidual and blood DC numbers were normalized to show the actual number of CD83+ cells per well. After 120 hours of culture at 37°C in 5% CO2, cultures were pulsed with 1 µCi of [3H]-thymidine (Amersham International, Arlington Heights, IL) per well for the final 16 hours before harvesting and liquid scintillation counting. All assays were performed in triplicate.
Statistical Analysis
Statistically significant differences between the anatomical localization of CD83+ and CD1a+ cells in immunohistochemistry was analyzed using the two-tailed Student’s t-test. Two sections per patient were assessed. There was no statistically significant difference between the distribution of the same cell type as determined by two independent assessors (P > 0.9). The mean values of MLR triplicates from each experiment were compared for statistical significance using the two-tailed Wilcoxon’s test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To identify DCs in early human pregnancy decidua, patient tissue
sections were stained with CD83 or CD1a and cytokeratin monoclonal
antibodies. A summary of the results of immunostaining is shown in
Table 2
. The cytokeratin staining allowed
the identification of endometrial glands and cytotrophoblasts and thus
the anatomical localization of the CD83+ and
CD1a+ cells in the decidua. For both antibodies,
the variation between each patient sample was statistically not
significant (P > 0.1). The numbers of
CD1a+ or CD83+ cells did
not change significantly relative to the week of gestation. Likewise
there was no statistically significant difference in
CD1a+ or CD83+ cells
between decidua parietalis and basalis. The CD83+
cells, as well as the CD1a+ cells, were of a
veiled shape typical for DCs, with long dendrites extending to the
surrounding tissue (Figure 1, a and b)
.
The mean density of CD83+ was 4.97 ± 1.88
SD per mm2
(n = 21). In
those tissue sections with clear visible lymphoid aggregates
(n = 18), 57% (2.55 ± 1.7 SD) of all
CD83+ cells were found within these cell
clusters, directly associated with CD3+ T cells
(Figure 1, d and f)
. In those tissue sections with clear visible
lymphatic vessels, as identified by their appearance as flattened
channels which were delimitated by a thin and irregular endothelial
wall (n = 10), 12.7% ± 6.9 SD of the total
CD83+ cells were located within those vessels
(Figure 1j)
. Most CD83+ cells not associated in
T-cell clusters or located in lymphatic vessels could be observed in
close vicinity to endometrial glands (1.22 ± 0.61 SD,
P < 0,005; Figure 1, b and d
). Only a minority of
CD83+ cells was scattered throughout the stroma
(0.64 ± 0.54 SD). The hysterectomy sample allowed us to determine
the anatomical localization of CD83+ cells in the
uterine wall which were localized with preference to the basal layer of
decidua (Figure 2
, scheme of uterine
wall). This location was found in the endometrium in cases of
nonpregnant uterus samples as well (data not shown).
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)
and most of those clusters contained less CD3+
cells than clusters with CD83+ cells (Figure 1, e and f)
. In those tissue sections with clear visible lymphoid vessels
(n = 10), 5% ± 0.6 SD of
CD1a+ cells could be observed in those vessels.
However, similar to CD83+ cells, non-T-cell
clustered CD1a+ cells were predominantly
associated with endometrial glands (0.91 ± 0.59,
P < 0.05; Figure 1a
). This intimate gland contact of
CD83+ as well as CD1a+
cells indicate that, in early human pregnancy, the endometrial glands
may be subject to a form of active immune response. Enrichment of CD83+ Cells from Decidua
For phenotypic and functional studies on this DC-like decidual
subset, the cells were enriched by immunomagnetic separation
techniques. Mononuclear cells were obtained from enzymatically digested
decidual tissue yielding an average of 3.6 ± 3.0 SD x
106
cells per gram of decidua
(n = 16) by density gradient centrifugation over
Histopaque. This decidual mononuclear cell fraction contained a
population of 0.3% ± 0.2 SD CD83+ cells. After
overnight culture, the nonadherent cell fraction contained 4.5% ± 3.2
SD CD83+ cells and was further enriched for DCs
by CD83+ selection. The cell fraction (mean,
2 ± 2 SD x 105
cells/g tissue;
n = 16) obtained by magnetic separation comprised
28.1% ± 4.3 SD CD83+ cells (corresponding to a
100-fold enrichment from fresh decidual mononuclear cells; Figure 3
). The weaker staining of isolated
CD83+ cells in comparison to those before
isolation may be because of the competitive binding of the CD83
antibody bound to the anti-mouse immunoglobulin MACS-beads used
for the magnetic separation. Determination of cell numbers by flow
cytometric analysis and counting of positively stained cells on
cytospins yielded comparable results (data not shown).
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Flow cytometric analysis of the nonadherent cell population after
overnight culture demonstrated that all CD83+
cells expressed CD45, CD40, and HLA-DR. Expression of CD14 at very low
levels and no co-expression of CD56 by CD83+
cells indicates the cells to be distinct from macrophages and LGLs
(Figure 4a)
. Within the
CD83- decidual cells, a population of
CD45+ cells was weakly positive for HLA-DR, CD40,
and CD14 and therefore may represent macrophages. Furthermore a
distinct population of CD56+ LGLs could be seen.
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. A minor population of ~12%
CD83-/HLA-DRlow cells
presumably represent immature DCs. Only a few cells, both
CD83- and CD83+, weakly
stained positive for CD14 and a small population of
CD83+ DCs co-stained with CD1a (5.2% ± 2.3
SD).
Cytospin specimens of isolated decidual cells enriched for DCs revealed
that CD83+ or HLA-DR+ cells
exhibited a typical DC morphology (Figure 1, h and i)
.
CD83+ cells were often clustered to multiple,
small lymphocytes (Figure 1g)
. The CD83+-enriched
fraction of cultured decidual cells included a subset of cells with
shape, morphology, and motility of DCs. Those cells were nonadherent,
of approximately 10 µm in diameter, and with an irregularly shaped
cell body. They were characterized by a varying number of long
dendrites on their surface which continually extended, retracted, and
bent in many directions giving a characteristic veiled appearance
(Figure 5)
. Decidual DCs were motile for
up to 2 days in cell culture, but had lost viability by day 3 (data not
shown).
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We next compared the ability of decidual
CD83+ enriched DCs (n = 6)
and blood monocyte-derived DCs (n = 5) to
stimulate the proliferation of allogeneic T cells. Blood-monocyte
derived DCs (BDCs) were analyzed by flow cytometry to confirm their
maturation state. They express CD83 in 59.2% ± 12.0 SD, HLA-DR in
85.48% ± 8.9 SD (Figure 6a)
, CD40 in
80.95% ± 9.4 SD, and CD80 in 25.5% ± 2.1 SD (data not shown).
Numbers of decidual DCs and BDCs used in the MLRs were normalized in
the presented graphs for the number of CD83+
cells. As shown in Figure 6
, approximately twofold higher numbers of
decidual DCs were required to stimulate a similar level of allogeneic
T-cell proliferation in the MLRs as compared to fully matured BDCs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have identified mature CD83+ DCs in decidual tissue by immunohistochemistry. The identification of CD1a+ cells in decidual sections with the same distribution pattern to CD83+ DCs, but in lower numbers, could possibly point to a heterogeneity of the DC population in this tissue. As described for skin19 and lymphoid tissue,28 decidua may harbor all three subsets of CD1a-/CD83+, CD1a+/CD83-, and CD1a+/CD83+ DCs. Whether the CD1a-/CD83+ cells within in tissue reflect mature DCs, or immature DCs expressing CD83 intracellularly, cannot be determined by immunohistochemistry. A typical feature of mature tissue DCs is their interaction with T cells19 and indeed, the decidual CD83+ DCs were often seen in close association with CD3+ T lymphocytes.
Localization of CD83+ and CD1a+ DCs in close vicinity to endometrial glands, preferentially to the basal layer of decidua (stratum basale), is similar to their distribution in nonpregnant endometrium (data not shown), where leukocytes were also concentrated in the stratum basale.29 This seems to be because of the fact that the upper layers of endometrium are repeatedly shed during menstruation leaving behind the stratum basale with its immunocompetent cells.29 This may help to avoid diminution in the immunological capacity of endometrium during the shedding phase, a distribution which continues in early pregnancy decidua. In 1984, Bulmer and Sunderland3 described the very occasional CD1a+ cell immediately beneath the endometrial gland endothelium in a few decidual tissue sections supporting our observations of the anatomical localization of decidual DCs.
The antigen presenting capacity of human decidual cells has been noted in previous publications.30-34 Oksenberg et al30 reported that first-trimester decidua-derived cells can act as accessory cells for mitogen-induced lymphoproliferation and for the presentation of soluble and particulate antigens to primed T cells. They suggested that dendritic-like cells are the main decidual APCs, but the precise identity of these cells remained unknown. In 1988, Dorman and Searle31 reported the alloantigen presenting capacity of cells in human decidual tissue and speculated that the decidual APCs may belong to the MHC class II+ DC lineage. However, those studies were performed on the adherent or complete fraction of isolated decidual cells. Therefore these earlier studies may demonstrate the antigen presenting capacity of adherent decidual macrophages, an assumption subsequently confirmed by Mizuno et al.32 In contrast to those previous publications, we have used the nonadherent cell fraction of cultured decidual cells to study DCs, because human DCs isolated from blood or tissue are known to be nonadherent.10,13,21 In addition these studies used cells cultured for several weeks before analysis,33,34 whereas we performed our cell isolation and analyses after only 1 night of culture.
The 10-fold increase in the number of CD83+ cells after the overnight culture step may reflect, in addition to the depletion of adherent contaminating cell types, the complete maturation of immature CD83- decidual DCs.35 However, this short culture time makes a culture-dependent differentiation process of monocytes into activated APCs, which could express CD83,35,36 unlikely. Additionally, as demonstrated in double-fluorescence analysis, the lack of CD14 expression argues against the possibility that these decidual CD83+ cells were activated monocytes. Only a few CD83-/HLA-DR+ cells were seen in the CD83-enriched cell fraction, indicating that this enrichment procedure seems to be suitable to remove nearly all non-DC that could express HLA-DR. The small population of CD83+/CD14low decidual DCs detected by FACS may represent a subset of DCs with a phenotype as reported for skin-derived populations37
Enrichment of DCs beyond 30% purity was made difficult because many T
cells were tightly clustered to DCs (see Figure 1g
), as previously
described for DC migrating from skin explants.38
T cells
remained clustered to DCs during the magnetic sorting procedure, even
at high concentrations of EDTA in the buffers used (unpublished
observations). However after labeling and FACS-acquisition, a fraction
of DC T-cell clusters were disrupted resulting in distinct
CD3+ and CD83+ populations.
Therefore future use of cell sorting by FACS technology may lead to
higher purity of decidual DCs. The small amount of available cells, a
fact we share with other studies handling DCs from nonlymphoid
tissue,39,40
minimizes the possibility of successive
enrichment steps to improve the percentage of
CD83+ cells.
Despite their impurity, the isolated decidual DC fractions were able to stimulate high levels of allogeneic T cell proliferation, although decidual DCs were not quite as potent allogeneic T cell stimulators as fully cytokine-matured BDCs. Because of the overnight cultivation step associated with the isolation of decidual DCs, this potent immunostimulatory property may not reflect the true in vivo situation. In addition, other APC populations may have been lost during the immunoselection of CD83+ cells. Therefore we cannot rule out that in vivo, in addition to the immunostimulatory DCs described here, other APC populations (perhaps with T cell tolerating capacity) may also exist in decidua.
In summary, among the many CD45+ leukocytes contained in decidual tissue, we have identified a subpopulation of CD40+/CD45+/CD83+/HLA-DR++, cells with morphological and functional features of typical mature DCs. The role of these potent APCs for immunoregulation of human pregnancy awaits further studies.
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Acknowledgements |
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Footnotes |
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Supported by grant Di-390/3–2 from the Deutsche Forschungsgemeinschaft (to J. D.) and grants Interdisziplinäres Zentrum für Klinische Forschung (IZKF)-A1 (to A. D. M.) and IZKF-A2 (to M. S.) from the University of Würzburg.
Accepted for publication March 8, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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