Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Mar;162(3):887-96.
doi: 10.1016/S0002-9440(10)63884-9.

Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy

Ulrike Kämmerer  1 , Andreas O Eggert, Michaela Kapp, Alexander D McLellan, Teunis B H Geijtenbeek, Johannes Dietl, Yvette van Kooyk, Eckhart Kämpgen
Affiliations

Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy

Ulrike Kämmerer et al. Am J Pathol. 2003 Mar.

Abstract

Intact human pregnancy can be regarded as an immunological paradox in that the maternal immune system accepts the allogeneic embryo without general immunosuppression. Because dendritic cell (DC) subsets could be involved in peripheral tolerance, the uterine mucosa (decidua) was investigated for DC populations. Here we describe the detailed immunohistochemical and functional characterization of HLA-DR-positive antigen-presenting cells (APCs) in early pregnancy decidua. In contrast to classical macrophages and CD83(+) DCs, which were found in comparable numbers in decidua and nonpregnant endometrium, only decidua harbored a significant population of HLA-DR(+)/DC-SIGN(+) APCs further phenotyped as CD14(+)/CD4(+)/CD68(+/-)/CD83(-)/CD25(-). These cells exhibited a remarkable proliferation rate (9.2 to 9.8% of all CD209(+) cells) by double staining with Ki67 and proliferating cell nuclear antigen. Unique within the DC-family, the majority of DC-SIGN(+) decidual APCs were observed in situ to have intimate contact with CD56(+)/CD16(-)/ICAM-3(+) decidual natural killer cells, another pregnancy-restricted cell population. In vitro, freshly isolated CD14(+)/DC-SIGN(+) decidual cells efficiently took up antigen, but could not stimulate naive allogeneic T cells at all. Treatment with an inflammatory cytokine cocktail resulted in down-regulation of antigen uptake capacity and evolving capacity to effectively stimulate resting T cells. Fluorescence-activated cell sorting analysis confirmed the maturation of CD14(+)/DC-SIGN(+) decidual cells into CD25(+)/CD83(+) mature DCs. In summary, this is the first identification of a uterine immature DC population expressing DC-SIGN, that appears only in pregnancy-associated tissue, has a high proliferation rate, and a conspicuous association with a natural killer subset.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Scatterplots of the density value of APCs in human first pregnancy decidua (A) and endometrium (B). Compared to endometrium the decidua contained significantly (P = 0.02) less CD83+ cells. Hardly any DC-SIGN+ cell was found in endometrium, whereas decidua displayed a remarkable population (P < 0.01). Bar, median of the columns; *, significant difference between endometrium and decidua.
Figure 2.
Figure 2.
Immunohistochemistry of decidual APCs in early human pregnancy. Violet, Vector VIP; brown, DAB; gray-blue, Vector SG; green, HistoGreen; red, AEC; blue, Vector APIII. A: DC-SIGN+ cells in decidua exhibit a DC-like veiled appearance with long dendrites extending into the surrounding tissue and connecting themselves in a network-like matter (violet, black arrows). B: Typical location of DC-SIGN+ cells (violet, white arrow) was in areas with spiral arteries (blue-gray, black arrow), but cells were also scattered throughout the tissue. DC-SIGN+ cells could often be seen in intimate contact to CD56+ LGLs (brown, white arrowhead). C: DC-SIGN+ cells (violet, white arrow) could be clearly distinguished by size and morphology from mature CD83+ DC (green, black arrow) that principally formed clusters with numerous lymphocytes. D: Co-staining of HLA-DR (red) and DC-SIGN+ (blue) demonstrated all DC-SIGN+ cells to express HLA-DR (purple, white arrow); single HLA-DR-positive cells were seen next to the double-positive cells (black arrow). Endogenous phosphatase activity stains vessels blue (*). E: Double staining with CD14 (red) revealed all DC-SIGN+ cells to express CD14+ (purple, white arrow); few CD14+ but DC-SIGN− cells could also be found (red, black arrow). F: All DC-SIGN+ cells co-stained with CD4 (green/brown, white arrow) next to a single CD4+ T cell (brown, black arrow). G: A high percentage of DC-SIGN+ cells (violet, white arrow) co-stained with CD68 (green) next to some single green-stained CD68+ macrophages (green, black arrow). H: DC-SIGN+ (violet, white arrow) and CD83+ DC (green, black arrow). I: HLA-DR+/DC-SIGN+ cells (violet/brown, white arrow) next to a HLA-DR+/DC-SIGN− cell (violet, black arrow). J: CD14+/DC-SIGN+ cells (purple, white arrow) surrounding a capillary vessel (blue, *) with one single CD14+ cell (red, black arrow). K: Two double CD4+/DC-SIGN+ decidual cells (green/brown). L: Perinuclear expression of CD68 (purple) in a DC-SIGN+ (brown) cell. Original magnifications: ×400 (A, C, D, F, G); ×160 (B); ×250 (E); ×1000 (H–L).
Figure 3.
Figure 3.
Interaction of proliferating DC-SIGN+ cells with CD56+ LGLs. A: Interference contrast clearly demonstrated the intimate contact between DC-SIGN+ cells (violet, white arrowhead) with CD56+ LGLs (brown, black arrow). B: DC-SIGN+ cells (green, white arrowhead) together with ICAM-3-positive cells (brown, arrow) that resemble the morphology of LGLs. C: Double labeling of ICAM-3 (blue) with CD56 (red) demonstrated all CD56+ cells to be ICAM3+ (purple); one single ICAM3+/CD56− cell was seen (blue, black arrow). White arrowheads indicate examples of ICAM3+/CD56+ LGLs. D: FACS analysis of isolated decidual lymphocytes. Left: A high percentage of the cells express ICAM-3. Right: All CD56+ LGLs co-express ICAM-3, representing the largest population of all ICAM-3-positive cells. E: Bar chart of proliferating DC-SIGN+ cells detected by double staining with Ki-67 (white bar, ∼9.2% of all DC-SIGN+ cells) and PCNA (black bar, ∼9.8%). F: Immunohistochemistry shows clear double staining for DC-SIGN (green) and PCNA (brown, white arrowhead) some PCNA−/DC-SIGN+ cells were seen (black arrow) next to proliferating non-DC-SIGN+ cells (black arrowhead). G: Simultaneous staining for DC-SIGN (green), CD56 (brown), and Ki-67 (violet) revealed a proliferating DC-SIGN+ cell (arrow) next to a proliferating LGL (white arrowhead) and closely attached to a nonproliferating LGL (black arrowhead). Original magnifications: ×400 (A, F); ×160 (B, C); ×1000 (G).
Figure 4.
Figure 4.
Double-staining FACS analysis of the phenotype of decidual cells. A: Surface staining of complete cells directly after isolation: ∼6% of all decidual cells were positive for DC-SIGN (top right) and these co-stained with CD14 (middle left) and at low level with HLA-DR (middle right). DC-SIGN+ cells did not co-stain with CD83 (bottom left) and CD25 (bottom right) and were clearly different from mature DCs. B: Intracellular staining of CD14+-enriched decidual cells: ∼50% of the CD14+ cells expressed DC-SIGN+ (left and middle) and also ∼50% of the DC-SIGN+ cells expressed the macrophage marker CD68 (right).
Figure 5.
Figure 5.
Bar charts of the comparison of APC surface marker expression on freshly isolated and cultured (15 hours in R10 with maturation cocktail) decidual CD14+ cells showing the mean of the fluorescence intensity (MFI, PE-channel). Whereas the MFI of DC-SIGN and CD14 were reduced to ∼50% (DC-SIGN) and to <20% (CD14) on maturation culture, the MFI of the maturation markers CD25 and CD83 dramatically increased, reflecting the capacity of the decidual CD14+ cells to efficiently mature into typical DCs. HLA-DR showed only a slight increase in the MFI and the isotype controls were negative in both populations.
Figure 6.
Figure 6.
Functional analysis of fresh (dAPC fresh) and cocktail matured (dAPC cult.) decidual CD14+ cells containing 50 to 70% DC-SIGN+ cells in comparison to monocyte-derived immature (MoDC immat.) and cocktail-matured (MoDC mature) DC. A: FITC-labeled ovalbumin (OVA-FITC) antigen uptake capacity by fresh dAPCs was fourfold higher than that of matured dAPCs, which displayed levels comparable to immature MoDC. B: Immunostimulatory activity of dAPC fresh and dAPC cult. in comparison to mature MoDC in a mixed lymphocyte reaction with MHC-mismatched responder T lymphocytes at the indicated ratios of APCs and T cells. Results are shown as the mean [3H]-thymidine uptake (proliferation) ± SEM for three samples each. [3H]-thymidine uptake of all APC and T-cell populations alone was <400 cpm and is not shown.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kammerer U, Schoppet M, McLellan AD, Kapp M, Huppertz HI, Kampgen E, Dietl J: Human decidua contains potent immunostimulatory CD83(+) dendritic cells. Am J Pathol 2000, 157:159-169 - PMC - PubMed
    1. Hart DN: Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 1997, 90:3245-3287 - PubMed
    1. Steinman RM: The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991, 9:271-296 - PubMed
    1. Inaba K, Metlay JP, Crowley MT, Steinman RM: Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med 1990, 172:631-640 - PMC - PubMed
    1. Thomas R, Davis LS, Lipsky PE: Comparative accessory cell function of human peripheral blood dendritic cells and monocytes. J Immunol 1993, 151:6840-6852 - PubMed

Publication types

Substances