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Female Reproductive Tract |
Research Group in Human Reproductive Immunobiology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1.7% of CD45+ cells in the isolates and had the phenotype of immature myeloid DCs. No CD1a+ Langerhans cells or CD123+ plasmacytoid DCs were detected. The decidual DCs were DC-SIGN-, DEC-205+, CD40+. Two subsets could be distinguished on the basis of relative expression of HLA-DR, which also differed in expression of DC-activation markers. The DCs were identified in situ by immunohistology by DEC-205 staining. Cells with dendritic processes were found scattered through both the decidua basalis (in which trophoblast cells are infiltrating) and the decidua parietalis. They were also visible in endothelial-lined spaces. This is the first study to identify and describe the phenotype and distribution of human decidual DCs.
decidua, immunology, implantation, pregnancy, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our aim in this study was to identify and characterize lin-, HLA-DR+ DCs in cell isolates obtained from normal human first-trimester decidua. We reported the presence of DCs in the human uterine mucosa with a phenotype characteristic of the immature myeloid lineage. In addition, using informative markers, we performed immunohistology to describe the morphology and localization of DCs in situ within the decidua.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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After informed consent, samples of first-trimester decidua (7–12 wk gestation) from women undergoing elective termination procedures were obtained from Addenbrooke's Hospital as previously described [10]. The study was approved by the Cambridge Local Research Ethics Committee. The tissues were washed in RPMI-1640 medium and samples for immunohistochemistry were snap frozen in Tissue-Tek OCT (Sakura, Torrance, CA) and stored at -70°C.
Isolation of Decidual Cells
Pieces of decidual tissue were chopped finely and digested with 0.5% collagenase type IV/20% heat-inactivated fetal calf serum overnight, or 2% collagenase type IV for 1 h at room temperature with gentle rotation. In some experiments the chopped tissue was dissociated mechanically using a syringe plunger to release cells more rapidly. This was achieved by grinding the tissue in a small volume of cold RPMI with a 20-ml syringe plunger, diluting with more cold RPMI, and collecting the supernatant after undissociated tissue pieces had settled. This was repeated four times and the supernatants pooled. To minimize activation of DCs during the isolation procedure, this mechanical method was also performed at 4°C.
A single cell suspension from either method was obtained by passing the supernatant through a series of cell separators to 40 µm and then layering the cells and performing density gradient separation on Lymphoprep (Axis-Shield, Oslo, Norway; 20 min, 600 x g) to remove red blood cells and debris. The mean total yield of cells was similar for each of the dissociation methods used and varied from 1.1 x 107 to 1.3 x 107 per sample. The cells obtained from either of the two dissociation methods were immediately labeled for analysis by flow cytometry. Comparisons were made between cells obtained from each method.
Immunofluorescence Labeling for Flow Cytometry
Freshly isolated DCs were initially incubated for 20 min with 40% heat-inactivated human AB serum to block Fc receptor (FcR) binding and then spun. A cocktail of phycoerythrin (PE)-conjugated antibodies to lineage-specific markers CD3 (T cells), CD14 (macrophages), CD56 (NK cells), and CD19 (B cells) (PE-lin) was added to the resuspended pellets in combination with Peridin chlorophyll protein (PerCP)–HLA-DR to allow gating of the lin-HLA-DR+ DC population for analysis. The monoclonal antibodies (mAbs) used are shown in Table 1. For direct labeling, fluorescein isothiocyanate (FITC)-conjugated antibodies were added to the FcR-blocked cells on ice in combination with the PE-lineage cocktail and PerCP-HLA-DR. All incubations were for 20 min on ice, and all washes were with ice-cold buffer. Cells were washed twice in ice-cold PBS/0.1% BSA, resuspended in the last drop, and fixed by the addition of 100 µl 2% paraformaldehyde. Cells were analyzed immediately or after overnight storage at 4°C. For indirect labeling of cells, unconjugated primary antibody was added to the FcR-blocked cells on ice. Cells were then washed twice in ice-cold buffer and labeled with FITC-conjugated goat anti-mouse IgG (Fab')2-specific antibody (Becton Dickinson) or FITC-goat anti-mouse IgM (Sigma, St. Louis, MO). Mouse IgG (200 µg/ml) was added to block free anti-mouse sites before subsequent labeling with the PE-lineage cocktail and PerCP-HLA-DR. Cells were washed and fixed as before. Unconjugated or directly conjugated (FITC, PE, PerCP) mouse isotype controls were used to set negatives for each class of antibody used. Fixed cells were analyzed using Facscan and Cellquest software (Becton Dickinson). Because of the low frequency of lin-HLA-DR+ DCs in the decidual samples, it was necessary to acquire a high number of events (50 000) within each of the scatter gates selected.
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Immunohistology
Acetone-fixed cryostat sections of decidua parietalis or decidua basalis were stained with the panel of antibodies in Table 1 using the avidin-biotin-peroxidase (Vectastain, Vector Laboratories, Peterborough, UK) technique as described previously [14]. Briefly, sections were blocked with 2% normal serum (of the species in which the secondary antibody was raised). Primary antibody was then applied at the optimal dilution followed by biotinylated horse anti-mouse IgG or biotinylated goat anti-mouse IgM (both from Vector Laboratories) and subsequently avidin-biotin-horseradish peroxidase (HRP) complex (Vectastain ABC, Vector Laboratories). Secondary antibodies were preadsorbed with 10% human AB serum before application. HRP was developed with diaminobenzidine (DAB) and sections were counterstained with Carrazzi hematoxylin.
The numbers of positive and negative cells were counted within five high-power view fields for each section. After random selection of each view field in turn on the first section, the same areas were identified for counting on adjacent serial sections. Areas of necrosis were disregarded. A mean number of 321 ± 188 cells was counted per high-power view field.
To identify vessels in the decidua, some sections were also double labeled with CD31 mAb (Dako, High Wycombe, UK) as follows. After development of the first test antibody with DAB, CD31 was applied followed by secondary biotinylated anti-mouse IgG and then ABC-alkaline phosphatase (Vector Laboratories). Endogenous alkaline phosphatase was blocked with levamisole and the sections developed with Red Substrate kit (Vector Laboratories).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To identify DCs in decidua, leukocyte preparations were obtained by two methods: by enzymic digestion with collagenase at room temperature (either overnight or after 1 h) or by a mechanical method (performed at room temperature or 4°C). Multicolor flow cytometry was used to analyze the cells in these preparations, and the scatter plots are shown for isolates obtained after overnight digestion with collagenase (Fig. 1A). The cells were stained with a lineage cocktail (lin) of mAbs to CD3, CD56, CD14, and CD19 versus HLA-DR, and analysis of the events falling in the scatter gate R1 of Figure 1A are shown in Figure 1B. The presence of considerable autofluorescence seen with unlabeled cells is typical of these DC preparations as has also been described in other tissue leukocyte preparations [15] (Fig. 1C). Despite this, three main populations were identified with lin/HLA-DR staining including a small but definite population of lin-HLA-DR+ decidual DCs (R2, Fig. 1B). The major population (R3) is lin+HLA-DR-, and there is also a substantial lin+HLA-DR+ population (R4). Backgating of the cells in R2, R3, and R4 indicates that the lin-HLA-DR+ DC (R2) are heterogeneous in size and granularity (Fig. 1F) similar to the lin+HLA-DR+ cells (R4) (Fig. 1E). In contrast, the lin+, HLA-DR- (R3) cells are smaller and less granulated (Fig. 1D).
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Following these initial observations defining the presence and scatter properties of decidual DCs, further samples were subsequently analyzed drawing two scatter gates, R1 and R2 (Fig. 2A). Leukocytes (CD45+ cells) accounted for 60% of cells in both of these two gates combined. The gate R2 contains a mixture of the three main populations but enhances for lin+HLA-DR+ and lin-HLA-DR+ cells (Fig. 2D), whereas the majority of cells in R1 are lin+HLA-DR- cells (Fig. 2B). The lin+HLA-DR+ cells falling in R2 are CD14+ tissue macrophages because omitting CD14 from the PE-lineage cocktail (Fig. 2E) results in almost complete loss of cells from the lin+HLA-DR+ upper right quadrant of Figure 2D. Staining with isotype-matched PerCP-IgG and FITC-IgG (Fig. 2C) and the lineage cocktail of mAbs with a control PerCP-IgG (Fig. 2F) confirms that the lin-HLA-DR+ events falling in the box drawn in the lower right quadrant in Figure 2D are specific. The majority of cells falling in R1 of Figure 2A are CD56bright NK cells (75% ± 4%, n = 3) (data not shown), which are the major leukocyte population in the decidua [3].
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By staining individually with mAbs to CD56, CD14, CD19, or CD3 and using lin-HLA-DR+ cells to define DCs, analysis of all cells falling in both gates R1 and R2 of Figure 2A together revealed that cells isolated using this method contain 44% ± 8% CD56+ NK cells (n = 3), 10% ± 4% CD14+ cells (n = 3), and 6% ± 3% CD3+ T cells (n = 8). CD19+ B cells were sparse (<1%) as expected from previous studies (data not shown). DCs (lin-HLA-DR+) account for 0.9% ± 0.2% (n = 8) of cells falling in gates R1 and R2. These findings indicate that DCs are present in the decidua and are in similar numbers to those described at other mucosal sites. The proportion of cells other than bone marrow-derived cells in gates R1 and R2 was about 40% in these isolates (lower left quadrant, Fig. 2B). These are mainly stromal cells together with small numbers of glandular epithelial and endothelial cells (unpublished observations).
Phenotype of DCs
Following identification of decidual DCs, further analysis of their phenotype was carried out using multicolor immunofluorescence with a panel of mAbs. To analyze expression of these markers on individual leukocyte populations, these mAbs were initially tested on decidual NK cells, macrophages, and T cells (data not shown). Both the phenotype of macrophages (lin+HLA-DR+) and DCs (lin-HLA-DR+) were then analyzed using the large scatter gate R2 (see Fig. 2A) (Figs. 3 and 4). Similar results were obtained whether the leukocytes were isolated by collagenase digestion (for 1 h or overnight) or mechanical means. The experiments were repeated at least three times and representative results are shown. In addition, the mean percent of positive cells from all data and the intensity of labeling with each mAb is tabulated in Table 2.
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As expected, both DCs and decidual CD14+ macrophages express CD45, CD4, and high levels of HLA class I molecules. CD16 was detectable only at low levels on macrophages but DCs were CD16-. Other markers previously found on DC subsets and macrophages were also analyzed. The integrin subunit CD11c has been used as a marker of the myeloid type of DCs and both decidual DCs and macrophages were found to express CD11c as well as the CD11b subunit. CD1a, a marker of Langerhan-type DCs, was negative on all leukocytes in the isolates. There was also no expression of CD123 (IL-3R), a marker of lymphoid plasmacytoid DCs. DCs have also been characterized by the expression of C-type lectin molecules DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) (CD209) and DEC-205 (CD205), which are both involved in antigen capture. The decidual DCs were consistently negative for DC-SIGN, but this marker was detected on macrophages. In contrast, DEC-205 was specifically expressed, albeit at low levels, on DCs but not on macrophages. The costimulatory molecule, CD40, and activation marker, CMRF-56, were found at low levels, and CMRF-44 and CMRF-58 (activation markers) at high levels on DCs. CD40 and CMRF-56 were not detected on macrophages, and CMRF-44 and CMRF-58 were found only at a lower level than on DCs. Toll-like receptor (TLR2) was negative, and CD83 (a later marker of activation) expression by both DCs and macrophages was negligible. To summarize, decidual DCs have the features of myeloid DCs and are HLA-DR+, CD11c+, DEC-205+, CD40+, DC-SIGN-, CD1a-, and CD123-.
Decidual DC Subsets
Based on the surface density of HLA-DR, decidual DCs could be divided into two subsets, HLA-DRhigh and HLA-DRmod. These subsets were clearly defined in most samples and were also phenotypically distinguishable with other markers (Fig. 5): 1) CD11c was expressed strongly by both populations; 2) CD86, CMRF-44, and CMRF-58 were all expressed at higher intensity on HLA DRhigh, compared with HLA-DRmod cells; and 3) CMRF-56 and CD40 were undetectable on the HLA-DRmod cells and found only at low levels on HLA-DRhigh cells.
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Identification of DCs in vivo
Immunohistology was performed to confirm the presence of DCs in vivo and identify their location in the mucosa. Our flow cytometric analyses have shown that the most useful markers to use are HLA-DR (macrophages and DCs), DC-SIGN, and CD14 (macrophages only) and DEC-205 (DCs only) (Fig. 6). There were large numbers of HLA-DR+ cells (Fig. 6A) in all tissue sections. CD14+ macrophages were localized as previously reported (Fig. 6B), and DC-SIGN+ cells were found in a similar location and distribution (Fig. 6C). These CD14+, HLA-DR+, and DC-SIGN+ cells were found around decidual glands subjacent to the glandular epithelium, scattered throughout the layers of the decidual stroma, and particularly abundant in the decidua basalis at the implantation site. The presence of interstitial trophoblast cells infiltrating between the stromal cells was confirmed by staining for HLA-G, whose expression is restricted to extravillous trophoblast [3] (Fig. 6E). In comparison with decidual macrophages, very few DCs, identified by DEC-205 reactivity, were detected, in keeping with the flow cytometric analysis of disaggregated cells (Fig. 6D). The DEC-205+ cells were found sparsely throughout the decidual stroma and frequently seen to have long cytoplasmic processes characteristic of DCs (Fig. 6G). An antibody to CD86 identified weakly positive cells in a pattern reminiscent to that seen with CD14. By comparing the numbers of positive cells in serial sections stained for CD86 and CD14, it was estimated that 40% of CD14+ cells were weakly CD86+.
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The findings were different at the implantation site in which 75% of CD14+ cells coexpressed CD86. However, at both sites there were small numbers of cells that stained particularly strongly for CD86+ (2% of total cells) (Fig. 6H), which mirrored the findings obtained by flow cytometry in which DCs express CD86 at greater intensity than macrophages (Figs. 3 and 4). In addition to those found in the stroma, HLA-DR+, DEC-205+, and CD86+ cells were often seen in spaces that on double labeling with a mAb to endothelium, CD31, were vessels. The intensity of CD31 is known to be less on lymphatics than venules [16], and we detected these leukocytes in spaces that had both weak and intense staining, suggesting they are in both lymphatics and venules (Fig. 6I).
Virtually no cells in the stroma stained for CD1a or CD123. Surprisingly, although by fluorescence-activated cell sorter analysis (FACS) both DCs and macrophages were specifically stained with CMRF-56 and showed strong expression of CMRF-44 and CMRF-58, only an occasional cell was labeled by any of these three antibodies in vivo. This could be due to rapid induction of these markers of DC activation during the isolation procedure [11,12]. It has been shown that extracting the cells at a temperature of 4°C will minimize this [17]. Using a modification of this method, we isolated decidual leukocytes on ice using a rapid mechanical method but still found similar expression of all markers including the activation markers by flow cytometric analysis, indicating that activation was initiated even under these conditions. CD83+ also labeled only occasional cells, which were identified in basal lymphoid aggregates and endothelial spaces. These results confirm the presence of DCs in the decidua in vivo and demonstrate they are close to fetal trophoblast cells at the implantation site.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1% of all cells in the isolates of all decidual cells and 1.7% of all CD45+ decidual leukocytes. This is the first report to define decidual DCs in the uterine mucosa using this classical method of identifying DC populations. We encountered similar problems with autofluorescence as described for cell isolates extracted from other solid tissues, but with appropriate controls and multicolor immunofluorescence, DCs were consistently and reliably identified. Furthermore, the different methods of extraction using enzymic digestion for varying lengths of time and temperature or by mechanical means did not yield significantly different results. Collagenase digestion has previously been shown not to remove surface markers from DCs [15, 18].
In humans, there are few reports describing the features of DCs freshly isolated from nonlymphoid tissues, although recently DCs from colonic mucosa have been described in a similar study to this one [15]. Virtually all the DCs isolated from decidua were CD11c+ and had other phenotypic features suggestive of immature myeloid DCs typical of most nonlymphoid tissues [1]. We never detected any CD11c- or CD123+ (IL-3R) cells in the lin-HLA-DR+ population, indicating that interferon (IFN)
/ß-producing plasmacytoid DCs are not present in decidua in keeping with observations that these cells are mainly a feature of T cell areas of secondary lymphoid tissue [19]. The CD11c+ cells were further characterized with other markers previously found on myeloid DCs. Virtually no CD1a cells were detected, and thus Langerhans cells typical of squamous epithelium [9] are not a feature of the uterus. DC-SIGN (CD209) was not expressed by lin-HLA-DR+ CD11c+ decidual cells, although it was found at low levels on the CD14+ macrophages. DC-SIGN+ cells have previously been found in decidua using polyclonal antibodies and immunohistology [20, 21]. Both these reports showed abundant cells that in number and distribution were more characteristic of macrophages than of the much sparser DCs. Using serial sections, we now confirm that CD14+ cells and DC-SIGN+ cells have a similar pattern of staining, and it seems, therefore, from our results combining flow cytometry and immunohistology that DC-SIGN is present on decidual macrophages but not on decidual DCs. This is consistent with other studies that show that DC-SIGN cannot be regarded as a specific DC marker because expression is also found in alveolar macrophages and dermal CD14+ cells but not on Langerhans cells [18, 22]. Induction of DC-SIGN expression during differentiation of blood monocytes to DCs has been shown to be closely regulated by cytokines, being positively induced by interleukin (IL)-4 and GM-CSF and negatively regulated by IFNs, transforming growth factor (TGF)ß, and dexamethasone [23]. The cytokine repertoire in the decidua does not include IL-4, although granulocyte-macrophage colony-stimulating factor, IFNs, and TGFß are present [3].
In keeping with features of immature myeloid DCs, we found low expression of DEC-205 (CD205) by flow cytometry. This was the only marker tested that was uniquely present on the lin-HLA-DR+ cells and not on lin+HLA-DR+ macrophages. The ligand for DEC-205, a C-type lectin, is unknown. Low levels are found on in vitro cultured immature monocyte-derived DCs, which increase markedly on activation [24, 25]. Functionally, DEC-205 is an endocytic receptor cycling antigens to late endosomes or lysosomes [26]. CD86 and CD40 were also expressed at low levels on the surface of isolated decidual DCs, which is consistent with an immature state.
Two decidual DC subsets were identified on the basis of intensity of HLA-DR+ staining. When phenotypic analysis was performed on these HLA-DRhigh and HLA-DRmod subsets, increased expression of CD86, CD11c, CD40, and DEC-205 were all found on the HLA-DRhigh subset, indicating that this population may be more mature. This indicates that maturation of some decidual DCs has occurred in vivo, but our immunohistological analysis suggests that at least some of the activation markers might have been induced during the extraction procedure. Although CMRF-44, CMRF-56, and CMRF-58 were found to be expressed by both macrophages and DCs even after rapid isolation of cells at 4°C, very few cells were identified in vivo. These are very early markers of DC activation and have previously been shown to be rapidly induced by extraction procedures [11, 12].
From the flow cytometric analysis, the only candidate marker for specific identification of DCs in vivo in tissue sections is DEC-205. Previous studies have attempted to define decidual DCs by immunohistology using CD83 [27], but this marker is expressed only on mature DCs and in our study was not detectable on the majority of decidual DCs or macrophages by flow cytometry. Older reports used CD1a as a marker for uterine mucosal DCs [28, 29] and showed occasional positive cells similar to our findings. However, expression of CD1a is restricted to Langherans cells in squamous epithelium, and indeed, in general, CD1a+ DCs seem not to be a feature of mucosal epithelial surfaces [9, 30]. Our findings show that DEC-205+ cells with visible dendritic processes are present scattered throughout the decidua parietalis and also at the implantation site at which they were seen in close proximity to fetal trophoblast cells. The paucity of cells detected was in keeping with the estimation that DCs are 1% of cells in our isolates. In contrast, CD14+ macrophages are abundant throughout the decidua, and serial sections stained for HLA-DR, CD14, and DC-SIGN showed a similar number of cells and distribution. Macrophages were frequently found subjacent to glands as well as interspersed between stromal cells and trophoblast. They were particularly abundant in the decidua basalis. Both DEC-205+ cells as well as HLA-DRbright and CD14+ cells were frequently seen in spaces lined by an indistinct cellular layer that was cytokeratin negative and stained weakly for CD31. Other lymphoid cells were only occasionally seen in these spaces. This observation has been noticed previously using a mAb to CD83 [27]. These cells are probably in transit in lymphatics (which stain less intensely for CD31 than veins), from the uterine mucosa to the draining pelvic lymph nodes. Continuous migration by decidual DCs would seem to be occurring.
The phenotype of the lin+HLA-DR+ CD14+ decidual macrophages and their relationship to lin-HLA-DR+ DCs is of interest. We could demonstrate only low or no expression of CD16 on the lin+HLA-DR+ cells. This might have been due to blocking of the CD16 Fc
RIII by the IgG component in the initial serum blocking step. However, CD14+ CD16- cells have been found subepithelially in the dermis and defined as a subset of dermal DCs [18]. In this study we referred to the decidual lin+HLA-DR CD14+ CD16- cells as macrophages, but it is possible that these cells are also a subset of DCs like those described by Turville et al. [18]. There is evidence that CD14+ cells, including those from the gut, may differentiate into DCs in vivo and in vitro [9, 15, 31].
The functions of DCs in decidua are unknown. At other epithelial surfaces, notably the gut, DCs may be pivotal in directing either the induction of tolerance to food antigens and commensals or initiating immune responses to pathogenic bacteria [6]. The continuous steady-state migration from the gut, lung, and skin that occurs with sampling of apoptotic cells and luminal antigens in the absence of inflammation results in only a partial maturation of DCs with upregulation of major histocompatibility complex (MHC) but no induction of high levels of costimulatory molecules [32–34]. In these situations DCs secrete IL-10 or TGFß, resulting in induction of regulatory T cells [5]. Migration without full maturation may result either from failure of activation of appropriate TLR and other receptors or from the local environmental milieu in which the immature DCs contact antigen. In the latter respect, it is interesting that many of the factors described to induce a "tolerogenic" type of DC or "alternatively activated" macrophages are present in abundance in the decidua. These include prostaglandin E2, vitamin D, TGFß and IL-10 [35–41].
The most interesting and unique function that decidual DCs may perform is in the sampling, processing, and presentation of trophoblast antigens that may express unusual MHC and MHC-like molecules as well as other paternally derived alloantigens. The older literature has suggested that decidua provide an "immunosuppressive" environment or that the hormonal state of pregnancy induces maternal Th2 responses. However, in mice, although there are several different models indicating T cell maternal tolerance to fetal antigens, the nature of the trophoblast MHC class I antigenic stimuli and the function of uterine DCs have not been studied. Indeed, the Th2 hypothesis must now be questioned, given a recent report that mice lacking four Th2 type cytokines can reproduce normally [42]. Other murine models have shown that blockage of the enzyme indoleamine 2,3-dioxygenase (IDO) causes fetal demise, and it has also been demonstrated recently that regulatory IDO-producing DCs inhibited T cell proliferation in humans [43, 44]. Indeed, it is striking that in both humans and mice, classical T cells are not recruited to the implantation site, even in failing or "rejecting" pregnancies. Stimulation of immature as opposed to mature DCs with alloantigens results in early upregulation of the inhibitory CTLA-4 on the responding T cells and production of IL-10 [45]. The nature and maturation state of the decidual DCs may thus be critical in T cell allorecognition of trophoblast. Alloantigen-specific T suppressor cells can also induce upregulation of immunoglobulin-like transcripts (ILT)3 and ILT4 inhibitory members of the ILT family rendering the DCs tolerogenic [46]. The trophoblast-specific class I molecule, HLA-G, can also inhibit murine DC function via interaction with PIR-B, a homologue of ILT4 [47]. Thus, several mechanisms involving decidual DCs may operate to prevent maternal T cell activation to trophoblast.
In addition, decidual DCs may interact with the large numbers of CD56bright CD16- NK cells present in first-trimester decidua. DCs can prime innate immunity by triggering NK cell functions, and decidual DCs could be important in activation of NK cells in the presence of trophoblast. Alternatively, DCs may be alerted to the presence of the stress of the implanting placenta by signals derived from NK cell recognition of specific trophoblast ligands [48]. The ability of DCs and NK cells to influence each other provides a link between the innate and adaptive immune responses, depending on the density of NK cells and the state of DC maturation [49]. Our demonstration of small numbers of immature DCs in the decidua in areas of dense NK cell infiltration provides a basis for exploration of DC function in utero in early pregnancy in relation to both maternal uterine NK cells and T cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Ashley Moffett, Research Group in Human Reproductive Immunobiology, Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, United Kingdom. FAX: + 44 1223 765065; am485{at}cam.ac.uk
Received: 25 March 2003.
First decision: 16 April 2003.
Accepted: 4 June 2003.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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S. N. Hudson Keenihan and S. A. Robertson Diversity in Phenotype and Steroid Hormone Dependence in Dendritic Cellsand Macrophages in the Mouse Uterus Biol Reprod, June 1, 2004; 70(6): 1562 - 1572. [Abstract] [Full Text] [PDF]
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