BIOLOGY OF REPRODUCTION 77, 590–598 (2007)

Published online before print 27 June 2007.

DOI 10.1095/biolreprod.107.060632

Minireview

Dendritic Cells: Key to Fetal Tolerance?1

Sandra M. Blois,2,4,5 Ulrike Kammerer,6 Catalina Alba Soto,7 Mareike C. Tometten,4 Valerie Shaikly,5
Gabriela Barrientos,4 Richard Jurd,5 Daniel Rukavina,8 Angus W. Thomson,9 Burghard F. Klapp,4
Nelson Fernández,3,5 and Petra C. Arck3,4

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University Medicine of Berlin,4 Charité Centrum 12, Internal Medicine and Dermatology, Campus Virchow, 13353
Berlin, Germany
Department of Biological Sciences,5 University of Essex, Wivenhoe Park, Colchester C04 3SQ, United Kingdom
Department of Gynaecology and Obstetrics,6 University of Würzburg, D-97080, Würzburg, Germany
Department of Microbiology,7 Parasitology and Immunology, School of Medicine, University of Buenos Aires,
C1121ABG Buenos Aires, Argentina
Department of Physiology and Immunology,8 Medical Faculty, University of Rijeka, 51000 Rijeka, Croatia
Thomas E. Starzl Transplantation Institute and Department of Surgery,9 University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania 15213
1
ABSTRACT INTRODUCTION
Pregnancy is a unique event in which a fetus, despite being The question as to why the placenta, despite the expression
genetically and immunologically different from the mother (a of paternally derived fetal alloantigens, is accepted by the
hemi-allograft), develops in the uterus. Successful pregnancy mother remains to be fully explained, although several immune
implies avoidance of rejection by the maternal immune system. tolerance mechanisms have been postulated [1–3].
Fetal and maternal immune cells come into direct contact at the Dendritic cells (DC) represent a population of cells with
decidua, which is a highly specialized mucous membrane that relevance to mucosal sites, such as the skin, airways, gut, and
plays a key role in fetal tolerance. Uterine dendritic cells (DC) decidua. This is because DC have the unique property of being
within the decidua have been implicated in pregnancy mainte-
able to induce both antigen-specific activation and suppression
nance. DC serve as antigen-presenting cells with the unique
ability to induce primary immune responses. Just as lymphocytes
during the immune response. DC may also play a role in
comprise different subsets, DC subsets have been identified that tolerance induction through the generation of T cells with
differentially control lymphocyte function. DC may also act to regulatory properties, which in turn limit the proliferation of
induce immunologic tolerance and regulation of T cell-mediated effector T cells [4, 5] or delete antigen-specific T cells [6, 7].
immunity. Current understanding of DC immunobiology within In the present review, we will discuss the role of DC subsets
the context of mammalian fetal-maternal tolerance is reviewed and their activation signals in the regulation of fetal-maternal
and discussed herein. tolerance. In this context, we will highlight the link between
decidua, dendritic cells, placenta, tolerance
DC and the cellular and molecular network components
involved in the biology of pregnancy, namely T cells,
cytokines, and hormones. These endocrine and immune signals
ultimately determine the maturation, differentiation, and
activation status of DC. In turn, these changes are responsible
for the dual capacity of DC to trigger an immune response that
1
Supported by grants from Charité (to S.M.B. and P.C.A.), DFG (KFO- is associated with fetal rejection and to promote cell tolerance
124/2 to U.K.), and the Croatian Ministry of Science (0376-0377 to at the fetal-maternal interface.
D.R.). S.M.B. is supported by Charité (Habilitations-Stipendium), and
C.A.S. and G.B. are supported by fellowships from CONICET and
DAAD, respectively. S.M.B., P.C.A., and D.R. are part of the EMBIC Immunobiology of Pregnancy
Network of Excellence, which is cofinanced by the European
Commission through the FP6 framework program ‘‘Life Science,
Fetal allograft hypothesis. The fetal-maternal relationship
Genomics and Biotechnology for Health.’’ is a unique immunologic phenomenon. Fetal tissues express
2
Correspondence: Sandra M. Blois, Charité Centrum 12, Internal alloantigens that are encoded by polymorphic MHC genes
Medicine and Dermatology, BMFZ, Raum 2.0547, Augustenburger inherited from the father. However, in a normal pregnancy,
Platz 1, 13353 Berlin, Germany. FAX: 49 30 450 553997; although the mother can raise antibodies against parental gene
e-mail: sandra.blois@charite.de or smblois@essex.ac.uk
3
These authors contributed equally to this work.
products, typically HLA allele-specific antibodies, these do not
elicit fetal rejection.
Initial studies in pregnancy invoking the classical allograft
Received: 5 February 2007. rejection theories implicated CD4 and CD8 T cells. This
First decision: 20 February 2007.
Accepted: 6 June 2007. concept has been expanded by the notion that NK cells are also
Ó 2007 by the Society for the Study of Reproduction, Inc. involved in rejection [8]. In addition, the role of cd T-cell
ISSN: 0006-3363. http://www.biolreprod.org recognition of trophoblasts has been documented in mice [9]
590
 DENDRITIC CELLS AND PREGNANCY TOLERANCE
and humans [10]. Moreover, NKT cells, most likely with
TCRcd, have been implicated in fetal rejection [11], as have
NKab T cells [12]. CD4 þ T cells that recognize paternal
antigens but not trophoblasts are presented by antigen-
presenting cells (APC) in decidual tissues [13, 14]. These
observations suggest that the properties of APC in the uterine
lining are important in modulating local immunity and
tolerance. No single mechanism to explain the so-called fetal-
maternal immunologic paradox has been identified. As in
tissue allografts, interactions between the adaptive and innate
immune systems, at both the cellular and molecular levels and
including cytokines, are required to regulate pregnancy to term.
The Th1 to Th2 ratio as a paradigm of fetal-maternal
tolerance. The maternal balance between Th1 and Th2-Th3
cytokines contributes to the success of pregnancy [15, 16]. It is
now accepted that during pregnancy, local changes in the
balance between Th1/Th2-Th3 cytokines occur within the
uterus and fetal-placental unit. Cytokine shifts influence
trophoblast cells and uterine immune cells (macrophages, NK
cells, and lymphocytes), which contribute to implantation of
the embryo, development of the placenta, and survival of the
fetus to term. The predominant cytokines at each stage of
gestation function both to limit maternal immune rejection of
the semi-allogeneic fetus, especially at the fetal-maternal
interface, and to facilitate the ongoing physiological processes
within the maternal reproductive tract. Furthermore, in
experimental models, cytokine imbalances with inappropriate
activation of macrophages and NK cells have been shown to be
detrimental to fetal survival [2].
We have previously reported [17] on the decisive roles
played by IL10 and IL12 in driving the acceptance or rejection
of the fetus. A strong, pregnancy-protective role for the Th2
cytokine IL10 is supported by data from mouse models, which
show that while purified exogenous IL10 administered during
pregnancy decreases resorption rates [18], injection of anti-
IL10 antibody enhances these rates. In support of these results,
injection of IL12 during early gestation has been found to
induce abortion and increase the levels of the proinflammatory
cytokines TNF and IFNG at the fetal-maternal interface [19].
Special Role of DC at Mucosal Interfaces
DC are particularly responsive to signals received from the
tissue microenvironment. In mucosal tissues, DC can acquire
unique features or phenotypes that are necessary for the
regulation of specific local immune functions, which include
tolerance to food antigens in the gastrointestinal tract, to
respiratory antigens in the airways, and protection against
pathogenic organisms [20]. The phenotypes of DC are
influenced by cytokines and anti-inflammatory mediators
produced by epithelial cells, either under physiological
conditions or in response to microbial signals [20].
Previously, we have proposed [17] that decidual DC are the
‘‘gatekeepers’’ of the uterine mucosal immune system, inducing
tolerance under normal physiological conditions. DC are also
sufficiently responsive to inflammatory stimuli to allow T-cell
priming and protective immunity when necessary. It is well
known that exposure to agents such as prostaglandin E2 (PGE2)
[21] polarizes the maturation of myeloid DC into Th2-
promoting DC, while other cytokines, such as transforming
growth factor b (TGFB), promote tolerogenic DC [22]. Both
PGE2 and TGFB are present at the fetal-maternal interface in
normal pregnancy and may be utilized by DC to regulate
placental health (Fig. 1). However, the assumption that
decidual DC have similar functions to mucosal DC needs to
be further investigated.
591
Tolerogenic DC: Different Maturation States or Different
Subsets?
The induction of tolerance by DC appears to contradict the
immunostimulatory function of these cells. However, a role for
DC in the induction of peripheral tolerance is supported by
several studies [23]. Two general hypotheses have been
proposed to explain how DC might maintain peripheral
tolerance. The first hypothesis is based on studies performed
by Dhodapkar et al. [24] and Steinman et al. [25], which
support the concept that antigen presentation by immature DC
induces tolerance, whereas antigen presentation by mature DC
induces immunity. This paradigm has been questioned, since
mature DC have also been found to induce CD4 T-cell
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tolerance [26, 27]. Current data suggest that steady-state DC
are sufficiently mature to express intermediate levels of MHC
class II and costimulatory molecules but are not yet activated to
the extent that they can induce an immune response [27–29].
Immunity occurs only in the context of infection-associated
signals, which induce full maturation of DC.
The second hypothesis suggests that unique DC subsets are
responsible for the induction of tolerance [30]. For example,
murine CD8A þ DC have been shown to act as a specialized
subset of tolerogenic or regulatory DC in experimental systems
of allograft rejection and in vivo studies [31, 32].
In support of the subset hypothesis, a DC subset with the
ability to prime type 1 regulatory T (Treg) cells has recently
been described. This subset produces IL10 upon stimulation,
exhibits a stable immature phenotype (CD45RBhigh ITGAXlow
MHC class IIintermediate CD86low) and plasmacytoid morphol-
ogy [33, 34].
Immature DC express CD200R2, type 2 receptors for
CD200, a glycoprotein with pregnancy-protective function,
which is expressed on trophoblast cells and in certain areas of
the deciduas on days 8–12 of pregnancy [35]. In DBA/2J-
mated CBA/J female mice [18] (a murine model in which
increased abortion rates can be induced by application of
lipopolysaccharide, Th1 cytokines or stress exposure), block-
ing CD200 greatly increases fetal rejection and conversely,
administering CD200Fc or CD200 þ splenocytes from BALB/c
mice reduces fetal rejection. Moreover, CD200 triggering of
DC induces a CD4 þIL2RA þ Treg population with suppressive
activity, as demonstrated by increased FOXP3 expression and
inhibition of mixed leukocyte reactions [36]. In line with this
finding, DBA/2J-mated CBA/J females that are exposed to
sound stress show elevated percentages of resident decidual
DC that express moderate levels of MHC II, CD80/86, and
ICAM1 on gestation Day 7.5 [17].
In humans, the number of mature CD83 þ DC increases in
the uterine mucosa during the late secretory phase of the
menstrual cycle in comparison to other endometrial phases
[37]. This is in contrast to first trimester decidua, in which the
vast majority of DC express CD209 (previously known as
DCSIGN), which is a marker for immature or inactivated DC
[38, 39]. Interestingly, freshly isolated decidual CD209 þ DC
take up antigen efficiently but are unable to stimulate naı̈ve
allogeneic T cells. However, when stimulated with an
inflammatory cytokine cocktail, these cells become mature
IL2RA þ/CD83þ DC with potent stimulatory capacity for
allogeneic T cells and are similar to those DC that are sparsely
distributed in early pregnancy decidua [39, 40].
Therefore, it can be hypothesized that the maturation state of
DC plays a role in the etiology of spontaneous pregnancy
failure. Indeed, the high abortion rates observed in the CBA/J 3
DBA/2J murine model are related to DC that exhibit a more
mature phenotype (higher expression of MHC class II, CD80,
592 BLOIS ET AL.

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FIG. 1. Hypothetical model of how dendritic cells (DC) regulate immune responses directed against the conceptus. During normal pregnancy,
tolerogenic stimuli from trophoblasts (Tro), progesterone (P), prostaglandin E2 (PGE2), vitamin D, and cells in the environment (e.g., NK cells and
macrophages) promote partial activation of the resident DC. This results in the production of anti-inflammatory cytokines (e.g., IL10), which promote the
induction of tolerance at the fetal-maternal interface, thereby activating different mechanisms, such as the production of pregnancy-protective Th2/Th3
cytokines and the generation of Treg, which enhance suppression of the immune system, thereby contributing to fetal tolerance.

and ICAM1), as compared to low-abortion-rate mice [41].
Deciduas from women with recurrent miscarriage at 8 wk of
gestation have been shown to contain significantly more CD83 þ
DC than gestational age-matched normal controls [42]. The
presence of mature DC correlates with higher abortion rates. It
is conceivable that these activated DC can overcome the
tolerance to paternal antigens and induce fetal rejection (Fig. 2).
Dendritic Cells Within the Decidual Cellular Environment
Cross-talk between DC and NK cells: two players in
innate immunity. Recent data have highlighted the cooperation
between DC and NK cells in the control/switch of innate
immunity. NCAM1 þþFCGR3 (formerly CD56 þþCD16)
uterine NK (uNK) cells represent the main population of
lymphoid cells in the uterine mucosa during early pregnancy
[43]. However, their number decreases from midgestation
onwards, and they are almost absent at term. Although the
interaction between trophoblast MHC class I molecules and
uNK cells is likely to provide the pivotal control for successful
implantation in humans [44], it is unclear how this process is
mediated. It is likely that uNK cells play a dual role in
reproduction: to monitor mucosal integrity throughout the
menstrual cycle, and to control trophoblast invasion during
pregnancy [43]. In contrast, during mouse pregnancy, uNK cells
accumulate on the mesometrial side of the placenta and play a
central role in decidualization [45]. Indeed, Il15tm1Imx/tm1Imx
mice, which lack uNK cells, present decidual abnormalities,
which include thickening of the arterial walls with luminal
narrowing and a hypocellular decidua basalis. However, uNK
cells are not required for successful pregnancy, since IL15/
mice have normal implantation and nonabortive pregnancies
[46].
Little is known about the potential interactions between DC
and NK cells under homeostatic resting conditions. However, it
has been shown that interaction between immature DC and
activated NK cells results in either DC maturation or cell death
[47]. The mechanisms that determine the death or maturation
outcome depend on a dynamic interplay between the ratio of
DC:NK cells and the DC maturation state [48]. Gerosa et al.
[49] have shown that the cross-talk between immature DC and
resting NK cells leads to cell activation only in the presence of
microbial stimuli. Furthermore, only under conditions of low
DC:NK ratios do DC-NK cell interactions result in NK
activation [50]. The cytokine pattern of DC activation after
interaction with uNK cells in response to antigenic stimuli
 DENDRITIC CELLS AND PREGNANCY TOLERANCE 593

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FIG. 2. During failure of gestation, massive infiltration of NK cells to the fetal-maternal interface and the production of IFNG by NK cells, together with
the presence of TNF-producing macrophages stimulate the full activation of DC and the production of inflammatory cytokines, particularly IL12. Antigen
presentation by mature DC induces Th1 cytokine production by lymphocytes, which results in the apoptosis of trophoblast cells and the Th1-type immune
bias of abortion.

could also influence the polarization of T-cell responses. There
may be physiopathologic conditions (i.e., spontaneous abor-
tion) under which disequilibrium of the ratio between uNK
cells and DC results in aberrant cell activation and perturbation
of the course of pregnancy (Fig. 2). In particular, it has been
reported that the vast majority of decidual immature DC are in
close contact with uNK cells, whereas the small number of
mature decidual DC are clustered with CD3 þ T cells, but not
with uNK cells. Moreover, in vitro studies have shown that
decidual CD83 þ DC cocultured with NCAM1 þ autologous
uNK cells stimulate the proliferation of NCAM1 þ cells in a
DC-dependent manner, increase KLRC1 inhibitory receptor,
and decrease KLRC2- and KLRK1-activating receptor expres-
sion [51].
DC-derived Cytokines and Pregnancy
Various types of DC-derived molecules with the ability to
polarize Th-cell responses have been identified. DC from IL12-
deficient mice fail to induce Th1 responses, which suggests a
critical role for IL12 family members (e.g., IL12, IL23, and
IL27) in DC-induced Th1 responses [52, 53]. Consistent with
this notion, murine CD8A þ DC, but not CD8A DC, can be
induced to produce large amounts of IL12 and IFNG [52, 54,
55]. These findings indicate that murine DC subsets that differ
in CD8A expression can prime naı̈ve Th cells to produce either
Th1 or Th2 cytokines, respectively [52, 56]. The mechanism by
which CD8A DC induce Th2 cytokines has not been
established, although IL13 [57] and IL10 [56] are suitable
candidates.
The activities of cytokines, such as IL10 and TGFB, as T-
cell polarizing factors are well-documented [58]. In accor-
dance, we have noted that the intracellular level of IL10 in
uterine DC is significantly higher than the level of IL12 during
most of the gestation period [17]. However, there is a transient
increase in the incidence of uterine CD8A þ DC in early
gestation, namely on Day 5.5, concomitant with a decrease in
the relative number of IL10-producing DC. Our current
paradigm is that DC have remarkable plasticity in their abilities
to induce Th1 or Th2 cytokines and to exhibit temporal
regulation and subtle discrimination of antigen stimuli [59].
This prompted us to suggest that in early gestation, fetal
antigens may be stimulating CD8A þ uterine DC to produce
Th1 cytokines, thus contributing to the inflammatory milieu
characteristic of the implantation period. At later stages, a
regulatory IL10 cytokine pattern predominates, which mediates
the communication between embryonic cells and maternal
594 BLOIS ET AL.
uterine cells and the maintenance of pregnancy [60–62].
Moreover, recent experiments have shown that uterine DC
from mice with high abortion rates display increased
expression of CD8A þ and increased IL12:IL10 ratios com-
pared to mice with a low incidence of fetal rejection [41].
Compared with mouse DC subtypes, human DC exhibit
considerable plasticity in response to cytokines and pathogens.
This feature makes it difficult to assign a function to each DC
lineage. In spite of this, recent findings indicate that myeloid
DC produce high levels of IL12 when stimulated with TNF or
CD40 ligand (CD40LG) and stimulate a Th1-skewed cytokine
profile in T cells, whereas fully mature plasmacytoid DC prime
T cells towards a Th2 cytokine profile [63]. Even though
protection from fetal rejection has been traditionally linked to a
Th2-type immune response, myeloid DC predominate in
human and mouse early pregnancy decidua [17, 38, 40].
Although these findings apparently contradict the Th1/Th2
paradigm, they are in line with the new importance given to the
state of activation over the lineage of resident DC. To date,
only one study has examined the expression of IL12 by
decidual DC, albeit in relation to peripheral blood DC in early
human pregnancy. The results show that IL12-producing
myeloid DC (ITGAX þ) or lymphoid DC (IL3RAþ) numbers
are significantly reduced in the decidua compared to the
peripheral blood. In addition, the level of IL12 secreted by
decidual myeloid cells stimulated with lipopolysaccharide
(LPS) or CD40LG was found to be significantly lower than
that secreted by peripheral blood counterparts [40]. Thus,
decidual DC can regulate the balance between Th1 and Th2
cytokines, resulting to the maintenance of pregnancy.
Consequences of Cross-Talk
Regulatory T cells. Treg block the functions of effector
CD4 þ and CD8 þ T cells. As a result, tolerance is achieved
[64]. Naturally occurring (i.e., thymically generated) CD4 þ
IL2RA þ Treg appear as mediators to prevent autoimmune
responses to self antigens, whereas Treg induced by antigenic
stimulation in the periphery (also referred to as ‘Tr1’ cells or
‘adaptive regulatory cells’) appear to be involved in the
maintenance of peripheral tolerance at mucosal surfaces [65,
66]. Mucosal tissues are faced with the constant challenge of
maintaining nonresponsiveness to nonself peptides (antigens),
which means that the immune system must employ potent
regulatory mechanisms. Several studies have demonstrated that
Treg can prevent graft rejection [67–69]. A similar situation
seems to occur during pregnancy, whereby the maternal
immune system tolerates paternal antigens expressed by the
fetus. Recently, it has been demonstrated that normal human
pregnancy is associated with an increase in the blood Treg cell
population. Analysis by stage of pregnancy has shown a
significant increase from the nonpregnant controls to the first
trimester and from the first trimester to the second trimester,
with no significant change from the second to third trimester.
The proportion of CD4 þ IL2RA þ T cells was significantly
lower 6–8 wk following delivery than during the third trimester
but remained higher than in nonpregnant controls [70]. In
addition, decidual CD4 þ IL2RA þ T cells represented 14% of
all CD4 þ T cells in the third trimester [71]. DC production of
IL10 may be critical for the generation of Treg [26, 33]. The
presence of decidua-resident, semimature DC subsets with
intermediate expression of MHC and secretion of IL10 [17, 38,
40] raises the question as to whether the tolerogenic function of
DC is achieved through the priming of Treg in the decidua.
Moreover, Gorczynski et al. [72] have shown that triggering
CD200R2, which is a pregnancy protective receptor that is
present on immature DC, leads to the generation of
CD4 þIL2RA þFOXP3þ Treg that have the ability to suppress
mixed lymphocyte reactions and allograft rejection.
Other regulatory T cells. In addition to CD4 þ Treg, CD8 þ
T cells may play a role in oral tolerance [73]. Furthermore,
CD8 þCD28FOXP3þ T-suppressor cells have recently been
reported to induce tolerogenic endothelial cells through the
induction of inhibitory receptors and the down-regulation of
costimulatory and adhesion molecules [74]. In murine
pregnancy, a CD8A þ cell subpopulation that prevents abortion
is present between gestation Days 4.5 and 8.5 [2, 75]. These
CD8A þ cells, which may coexpress the TCRcd, appear to play
a crucial role in the regulation of the Th1/Th2 balance [2, 76].
Our studies suggest that during stress-challenged pregnancy,
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there is a decrease in uterine CD8A þ cells. Since we observed a
low fetal rejection index when CD8A þ cells were restored by
dydrogesterone (a progesterone derivate product), it appears
that these cells are highly regulated by the adequate levels of
progesterone at the fetal-maternal interface [77]. Moreover,
depletion of CD8A þ cells abrogated the protective effect of
dydrogesterone in mice undergoing stress-challenged pregnan-
cy. Although they have not been classified as ‘‘professional’’
regulatory cells, these uterine CD8A þ cells may be involved in
the suppression of immune responses.
Tryptophan 2,3-dioxygenase (TDO2) and indoleamine
2,3-dioxygenase (INDO). Tryptophan catabolism is one of
the many mechanisms involved in tolerance [78]. This essential
amino acid is used by vertebrates in protein synthesis and is a
precursor to serotonin, melatonin, kynurenine, and quinolinic
acid. Moreover, some tryptophan catabolites induce apoptosis
of T cells [79]. Expression of INDO is induced by IFNG in
many tissues and in certain types of activated macrophages and
DC, suggesting a role for INDO in the regulation of immune
responses [80].
Tatsumi et al. [81] have demonstrated that TDO2 is induced
in endometrial stromal cells concomitant with decidualization,
which suggests its involvement in the implantation process by
regulating the tryptophan level at the implantation site. On the
other hand, INDO is expressed in the syncytial trophoblast and
defends the conceptus against rejection by reducing the
tryptophan level and suppressing T-cell activity. Several
animal studies that have investigated the role of INDO in
murine pregnancy have given contradictory results. Pharma-
cologic inhibition of INDO activity results in rejection of
allogeneic fetuses by the maternal immune system [13].
However, Indotm1Alm/tm1Alm mice do not exhibit fetal rejection
in allogeneic matings, which suggests that INDO is not an
essential mechanism for tolerance in the context of pregnancy
[82]. Moreover, Mackler et al. [83] have shown that INDO is
not expressed in murine trophoblasts but it is expressed in
stromal cells of the decidua basalis and metrial gland. In
contrast, Baban et al. [82] have shown that INDO expression is
restricted to the perinuclear regions of primary trophoblast
giant cells at the middle stage of mouse gestation. Further
investigations are needed to clarify the role of INDO in
pregnancy maintenance.
Influence of the Endocrine System During Pregnancy
Dendritic cells and steroid hormones. An excellent body
of literature exists regarding the influence of steroid hormone
pathways on immune cell populations [84, 85]. Progesterone
probably contributes to the natural suppression of cell-mediated
immunity that accompanies pregnancy and allows the fetus to
be tolerated during gestation. Progesterone acts through two
isoforms of the progesterone receptor (PGR) [86]. Until
 DENDRITIC CELLS AND PREGNANCY TOLERANCE
recently, the consensus has been that PGR is induced by
estrogen, and that many of the effects of progesterone can be
attributed to the combined effects of estrogen and progesterone.
Interestingly, it has been demonstrated that progesterone is
essential for the induction of uterine decidualization, since this
process fails to occur in mice that lack the Pgr gene [87, 88].
Indeed, Liu et al. [89] have reported that estrogen decreases the
production of proinflammatory cytokines TNF, IFNG, and
IL12 in mature DC. High estrogen levels at the fetal-maternal
interface could influence uterine DC to reduce inflammatory
cytokine production.
Recent studies have implicated progesterone in the
modulation of DC differentiation, maturation, and function.
Liang et al. [90] have shown that progesterone inhibits immune
responses by producing more immature bone marrow (BM)-
derived DC in mice. The addition of progesterone to BM-
derived DC cultures results in significantly increased IL10
production and decreased TNF production. In addition, Butts et
al. [91] have found that progesterone at concentrations similar
to those occurring during the menstrual cycle or pregnancy has
a crucial effect on rat BM-derived mature DC by modulating
the ability of these cells to function as stimulators of
proinflammatory responses. In vitro studies have shown that
DC derived from the decidua of pregnant women increase their
CD83 and HLADR expression levels when treated with
progesterone at levels similar to those present during early
pregnancy [92].
Vitamin D and PGE2: novel modulators? Experimental
evidence suggests that vitamin D may play a role in maternal-
conceptus cross-talk. Besides its classical activity, the active
form of vitamin D, 1,25-dihydroxyvitamin D3 or 1,25(OH)2D3
has well-known immunomodulatory and antiproliferative
properties on human uNK cells [93]. Female fertility seems
to be markedly reduced in vitamin D-deficient murine models.
Both decidua and trophoblast cells express vitamin D receptor
(VDR), as well as CYP27B1 (previously known as 25(OH)D
1a-hydroxylase), which suggests an autocrine or paracrine role
for 1,25(OH)2D3 within these tissues [94]. In particular,
Zehnder et al. [95] have postulated that local activation of
vitamin D influences implantation, either through the estab-
lished immunomodulatory effects of 1,25(OH)2D3 or via the
regulation of specific target genes associated with implantation.
Indeed, 1,25(OH)2D3 regulates developmental target genes,
such as the homeobox (Hox) genes. In particular, the Hoxa10
gene has been shown to be intimately associated with
implantation [96].
Another immunomodulatory molecule that is present at the
fetal-maternal interface is PGE2. PGE2 suppresses a number of
T-cell reactions (e.g., cellular cytotoxicity and T-cell and killer-
cell activity) and promotes the development of DC with low
capacities to produce IL12, which supports the generation of
Th2 cells. Harizi et al. [97] have demonstrated that exoge-
nously added or endogenously released PGE2 acts on DC by
inducing endogenous IL10, which in turn suppresses IL12
production and alters antigen presentation through the
inhibition of MHC class II protein expression. As vitamin D
and PGE2 are both present in decidua, these molecules may
inhibit IL12 production by the uterine DC, thereby shifting the
cytokine balance to a tolerogenic state at the fetal-maternal
interface.
DC and Promotion of Transplant Tolerance
Evidence implicating DC as the main immunological
stimulus for graft rejection has been provided by the renal
allograft ‘‘parking’’ experiments of Lechler and Batchelor [98].
595
Subsequently, Larsen et al. [99] were the first to show that DC
trafficked from heart allografts to recipient spleens, which in
nonimmunosuppressed hosts is associated with rejection,
concomitant with the disappearance of the donor DC. Studies
conducted by Lu et al. [100] have revealed that donor-derived
myeloid DC persist in and can be propagated from the BM of
mice that accepted fully mismatched (liver) allografts without
immunosuppressive therapy. This cannot be achieved with
animals that acutely reject heart grafts from the same donor
strain [100], unless both donor BM cells and immunosuppres-
sive therapy are administered [101]. Further studies have
shown that immature donor myeloid DC, which are deficient in
surface costimulatory molecules, can induce alloantigen-
specific T-cell hyporesponsiveness in vitro [102]. More
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significantly, several groups have shown that when adminis-
tered before, during or even after transplantation, immature
donor DC prolong MHC-mismatched allograft (including skin
graft) survival. In some instances, indefinite donor-specific
graft survival is achieved [103–110]. Recently, it has been
shown that TGFB-treated (‘alternatively-activated’) IL10 þ DC
resist phenotypic and functional maturation in response to
TLR4 ligation and induce long-term heart allograft survival
when coadministered with a single dose of CTLA4-Ig. Graft
survival is associated with Treg infiltration and the absence of
vasculopathy [111]. There is also evidence that persistence of
donor-derived DC may be important for the long-term
maintenance of transplantation tolerance, as well as for the
prevention of chronic rejection of heart allografts [112].
Collectively, these findings suggest that donor-derived DC,
most likely but not exclusively at an immature/progenitor
stage, can subvert recipient T-cell responses to alloantigens,
through as yet ill-defined mechanisms. Although comparative-
ly little research has been performed using syngeneic/
autologous DC to subvert the indirect pathway, recent animal
studies support the feasibility of this approach. Thus, Lechler’s
group [109] has shown that indefinite organ graft survival can
be achieved in the absence of chronic rejection in rats that are
receiving pharmacologically modified myeloid DC that express
donor and recipient MHC antigens and only a short course of
peri-operative cyclosporine (to control the direct pathway).
Significantly, this effect is associated with the induction of
indirect-pathway Treg. It appears that antigen-specific Treg can
be induced under systemic tolerogenic regimens by plasmacy-
toid DC that acquire alloantigen in the graft and traffic to
secondary lymphoid tissues [113].
CONCLUSION
Understanding the immunological paradox of maternal
tolerance towards the fetal allograft is of great importance.
The complexity of the uterine network clearly indicates that
successful pregnancy does not rely entirely on immunological
factors. DC appear to be key regulators of pregnancy,
involving both innate and adaptive mechanisms. Decidual
DC likely function to co-ordinate the spatial and temporal
immunological shifts necessary for implantation and the
progression of pregnancy.
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