Biomedicine & Pharmacotherapy 88 (2017) 6173

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Immune regulatory network in successful pregnancy and reproductive

failures
Mahnaz Ghaebia,b,c , Mohammad Nourid, Aliyeh Ghasemzadehe, Laya Farzadie ,
Farhad Jadidi-Niaragha,b,f , Majid Ahmadia,b , Mehdi Yousea,b,c,*
a
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
b
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
c
Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
d
Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
e
Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
f
Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

A R T I C L E I N F O A B S T R A C T

Article history:
Received 27 November 2016 Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful
Received in revised form 27 December 2016 pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal
Accepted 2 January 2017 leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important
components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an
Keywords: important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies,
Maternal immune system their frequency and function are reduced in reproductive defects such as recurrent miscarriage and
Treg preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been
gdT cell shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine.
Breg
Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells
NKT
MDSCs that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T
Pregnancy (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal
tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg,
gd T cell, Breg, MDSC, and NKT cells in pregnancy outcome.
2017 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Suppressor and regulatory T cells in pregnancy . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Treg changes during normal and disturbed pregnancies .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. Interaction between Tregs and DCs . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.3. Interaction between Treg and NK cells . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.4. Interaction between Tregs and TH17 . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.5. Functional mechanisms of Tregs in normal pregnancy ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Regulatory gdT cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Bregs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5. NKT cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6. MDSCs in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

* Corresponding author at: Drug Applied Research Center, Tabriz University of

Medical Sciences, Tabriz, Iran.
E-mail address: Youseme@tbzmed.ac.ir (M. Youse).

http://dx.doi.org/10.1016/j.biopha.2017.01.016
0753-3322/ 2017 Elsevier Masson SAS. All rights reserved.
62 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173
1. Introduction
Since the fetus is a semiallograft, a successful pregnancy needs
mechanisms to prevent allograft rejection [1]. Polymorphic genes
inherited from the father generate alloantigenes which provoke
the maternal immune responses leading to fetal rejection.
Adaptation of immune system is crucial to prevent rejection of
the semi-allogeneic conceptus in pregnancy [2]. Dysregulation of
immune responses may lead to reproductive failures such as
recurrent pregnancy loss (RPL), implantation failure, preterm birth,
intrauterine fetal growth restriction and preeclampsia [3]. The
most common pregnancy problems are miscarriage and pre-
eclampsia [4,5]. Miscarriage occurs in about 15% of the cases, and
recurrent miscarriages in 25% [4]. Although the exact cause of
about 50% of recurrent miscarriages remains elusive, however
immunological rejection may account for most of these unex-
plained cases of pregnancy loss [68]. Several immunological
mechanisms have been proposed for tolerance to the semi-
allogeneic fetus. It is suggested that miscarriage occurs in mice and
humans when these mechanisms become dysregulated [9]. Since
maternal alloreactive lymphocytes are not systemically depleted,
the local mechanisms may act to avoid maternal immune attack
[10]. Fetal trophoblast with its special features including low
tryptophan levels, the expression of HLA-G/C and so lack of
activation of natural killer (NK) cells, absence of classical HLA Class
I and Class II trophoblast expression, high progesterone levels and
antiidiotype network modulation plays an important role in
immune tolerance to the fetus [1115]. In addition, it has been
demonstrated that maternal T cell recognition of fetal antigens
occurs in an indirect manner that means fetal allograft is ignored
by directly alloreactive T cells that cause acute transplant rejection
[16]. Despite the presence of various mechanisms in immune
evasion, maternal adaptive immune system can recognize paternal
alloantigens [2], as a study published in 2003 has reported that
pregnancy induces cytotoxic T cells specic for minor histocom-
patibility antigens [17]. Fetal specic adaptive immune responses
develop as a consequence of normal human pregnancy and unlike
the murine models, T cells specic for fetal alloantigens are not
deleted during human pregnancy [6]. So, immunoregulatory
mechanisms are requested to suppress activated fetal-specic T
lymphocytes. Maternal recognition of embryo-derived paternal
antigens has been demonstrated to occur in several ways.
Trophoblast tissue is the main contact region between mother
and fetus, but there is a wide micro-chimerism between them
[18,19]. It has been found that fetal cells are present in mothers
blood throughout the pregnancy and for a long time further.
Moreover, maternal cells have been detected in the progeny long
after delivery and remain at adulthood. Trophoblast is clearly
penetrable, not impenetrable physical barrier through which the
exchange of cells between mother and fetus takes place [2].
Interestingly, microvesicles containing fetal antigens are shed from
human placenta [20]. It has been demonstrated that leukocytes
which are important constituents of decidua and myometrium
affect multiple events during pregnancy, including implantation,
maternal tolerance to the semiallogeneic fetus, defense against
infections, and the induction of labor [21]. Leukocytes comprise
around 3040% of the total endometrial cells in early to
midpregnancy uteri [22]. Leukocytes have been found even in
the proliferative and early secretory phases of menstrual cycle in
nonpregnant endometria [23]. To elucidate the maternal aware-
ness of paternal-derived alloantigens, it has been proposed that
antiallogenic T cells are anergized during pregnancy [24]. But the
maternal immune system maintains the ability to respond to
paternal alloantigens during pregnancy [2]. Fetal-specic cells
demonstrated an effector memory phenotype and were broadly
functional in a study conducted by Lissauer and coworkers. Fetal
specic cells show proliferation, IFNg secretion and ability to lyse
target cells following recognition of processed male antigens [6].
Involvement of suppressor cells in the prevention of rejection of
the fetus was initially suggested based on mixed lymphocyte
reactions using splenocytes from either pregnant or virgin females
[25]. The predominance of Th2 type immunity in Th1/Th2 balance
has been proposed as a possible strategy for survival of the fetus in
the uterus [26]. Increased Th2 polarization in maternal peripheral
blood mononuclear cells (PBMCs) and decreased IFNg secretion
are associated with the normal pregnancy [27]. Women with RPL
show increased Th1 to Th2 cell ratio and increased IFNg production
compared with normal healthy group [28]. In addition, Th17 cells
are positively associated with idiopathic RPL [29]. The necessity of
Th2 cytokines in a normal pregnancy is unknown, since studies on
genetically-decient mice which lack the ability to secret Th2
cytokines did not always lead to miscarriage [15,30]. Therefore,
other mechanisms such as the function of regulatory cells regulate
alloreactive Th1 cells [15]. Increased number of Treg in normal
pregnancy and impaired function and frequency of these cells
during pregnancy failures demonstrate importance of regulatory
cells in pregnancy [15]. Recently the other immune cell popula-
tions with regulatory effects have been reported to exist in
fetomaternal interface and play critical roles in pregnancy
maintenance.
2. Suppressor and regulatory T cells in pregnancy
Based on phenotype, cytokine secretion and tissue origin, three
subsets of CD4+ regulatory T (Treg) cells with different suppressive
functions have been distinguished [30]. These are type 1 regulatory
T cells (Tr1), Th3 cells, and CD4+CD25+ regulatory T-cells (Treg
cells) [31]. CD8+/Foxp3+ T cells with regulatory features have also
been described, however their function, ontogeny and regulation
are still unknown [32]. Tr1 cells are CD4+CD25+Foxp3_ T cells
induced by IL-10 which also exert their suppressive activity by
secretion of IL-10 [33]. They were at rst characterized as
suppressors of antigen-specic immune responses in mouse
models of inammatory bowel disease [34]. Th3 cells were
initially discovered in mice as inducers of oral tolerance that inhibit
immunity by synthesis of transforming growth factor-b (TGF-b),
IL-10 and IL-4 [35]. Among these three cell subsets,
CD4+CD25+Foxp3+ Treg cells obviously have essential role in a
reproduction. Tregs are described as a distinct cell subset on the
basis of surface phenotype and functional properties [36]. They
constitute 510% of CD4+ T-cells in rodents and 13% of CD4+ T-
cells in humans [37]. Although Tr1 and Th3 cells are present in the
uterus [38], the precise role of these cells in pregnancy is unknown
as White et al. showed that allogenic pregnancy is not compro-
mised in IL-10 null mutant mice [39]. On the other hand, Robertson
et al. has reported that IL-10 null mutant mice are susceptible to
inammation-induced fetal loss [40]. It has been demonstrated
that HLA-G expressed on EVT cell which modulates alloreactive T
cells induces generation of IL-10-producing Tr1 cells, in an IL10-
dependent pathway [41,42]. Membrane-bound HLA-G and its
inhibitory receptor Ig-like transcript (ILT)-4 are upregulated in
chronic antigen stimulation in the presence of IL-10, suggesting a
positive feedback loop in maintaining maternal tolerance by Tr1
and HLA-G [42]. Recently, DC-10 cells as a subset of human DCs
which produce IL-10 has been characterized in the peripheral
blood. DC-10 cells express surface HLA-G, ILT2, ILT3, ILT4 and
secrete IL10 at high levels. In vitro experiments have shown that
DC-10 cells induce IL10-producing Tr1 cells through IL10-depen-
dant ILT4/HLA-G pathway [43]. It has been shown that a higher
frequency of DC-10 is present in human decidua than in peripheral
blood of pregnant women, suggesting the possible role of DC-10 in
conjunction with inducing IL10-producing Tr1 cells in
 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173
fetomaternal tolerance [44]. The necessity of Th3 cells in
pregnancy needs more investigations, because TGFb null mutant
mice do not remain alive by the reproductive age and suffer from
non-immune-related reproductive disorders [45].
2.1. Treg changes during normal and disturbed pregnancies
It is observed that during pregnancy Treg cells in decidua are
increased [4648], and have a stable suppressive phenotype
[48,49]. Women suffering from repeated miscarriage (RM) were
shown to have a reduced frequency [50,51], and function of Treg
cells [51]. Sasaki et al. [46] observed that the population of
CD4+CD25bright cells in decidua of normal early pregnancy was
signicantly higher than peripheral blood and this was not seen in
the patients with spontaneous abortion. Several studies have
reported that in the pre-eclamptic patients the frequency of
CD4+CD25high T cells is signicantly reduced in both the
peripheral blood and decidua compared with normal pregnant
women [52,53]. Reduced expression of Foxp3 mRNA in endome-
trium has also been reported in primary unexplained infertility
[54], indicating that defect in T cell differentiation into Treg in
uterus or insufcient migration of Tregs before conception may
also impair the ability to become pregnant [36]. The massive
increase in circulating Treg cells during early pregnancy, reaching
highest level in 2nd trimester when trophoblast invasion to
decidua is maximal, suggests that these cells may regulate immune
responses against fetoplacental graft in the uterus [55].
CD4+CD25+ Foxp3+ Treg cells may be benecial as a marker to
assess miscarriage risk in pregnant women. Winger and Reed
(2011) identied that Treg values of 1.0% or more seem to dene
groups that may require no therapeutic procedure, while values
below 0.7% may identify patients where therapeutic intervention
may salvage threatened pregnancies [56].
2.2. Interaction between Tregs and DCs
Activation and expansion of Treg cells need interaction with a
specic type of DCs termed tolerogenic DCs [57]. Four subsets of
antigen presenting cells have been identied in human decidua
[58]. Heikkinen et al. have characterized decidual CD14+ macro-
phages with features resembling the phenotype of immature DCs
[59]. Mature CD83+ DCs, CD14+ DC-SIGN+ cells and small
population of immature myeloid DCs are other subtypes present
in early human decidua [60,61]. The IL-10 producing CD14+
decidual cells [59] and immature DCs [60] have ability to induce
differentiation of Treg cells in the decidua. Tolerogenic DCs (tDC)
are characterized with their immature or semi-mature phenotype,
lack of expression of the Th1-inducing cytokine IL-12 and the
altered expression of co-stimulatory molecules CD80 and CD86
[57]. They also express surface CD8 molecule and indoleamine 2,3-
dioxygenase (IDO) [62]. Even mature DCs can induce Treg cell
proliferation if differentiated appropriately [63]. Plasmacytoid DCs
are able to produce IDO, activate resting Tregs, participate in
converting CD4+CD25
T-cells into CD4+CD25+Foxp3+ Tregs and
maintaining Treg suppressive activity both in mice [64] and in
humans [65]. Expression of IDO may be induced through ligation of
the costimulatory molecule B7 (CD80/CD86) on DCs by CTLA-4, a
molecule expressed on Tregs, thereby can also hinder DCs capacity
to activate effector T cell functions [60,66]. The cytokines in the
milieu are a pivotal factor in controlling DCs phenotype and then
signals received by T cells. In the presence of TGFb, IL-10,
granulocyte-macrophage colony-stimulating factor (GM-CSF)
and IL-4, differentiated DCs have phenotypic and functional
features of immature DCs and induce CD4+CD25+ Treg cells
[67]. Later studies showed direct signaling between Treg cells and
DCs that gives DCs tolerogenic properties [68]. More recently it has
63
been recognized that IDO generates 3-hydroxyanthranillic acid,
which drives the generation of Treg cells [62,69].
2.3. Interaction between Treg and NK cells
There is increasing evidence that the interaction between NK
and Treg cells could be helpful during pregnancy. Needing to an
immunosuppressive environment for a successful process of
implantation of the embryo to decidua and tolerance of maternal
immune system to the fetus may be the reason for this observation
[70]. Interestingly, 70% of all human decidual lymphocytes are NK
cells, termed as uterine or decidual NK (dNK) cells [71]. dNK cells
are CD56brightCD16
CD3
cells, which express killer cell
immunoglobulin-like receptors (KIR) and show reduced killing
capacity despite the presence of cytolytic granules [72]. It has been
shown that dNK cells have potential to promote Treg cell
proliferation through interacting with CD14+ cells in decidua.
The crosstalk between dNK cells and decidual myelomonocytic
CD14+ cells have been shown in some experiments, which results
in the production of IFN-g that induces IDO expression in dCD14+
cells. The dCD14+ cells could induce Treg cell generation via the
effects of IDO and TGFb [73]. TGFb is an important cytokine for the
differentiation of extrathymic Treg cells. Interestingly, dNK cells
produce TGFb at feto-maternal interface, and this TGFb-producing
cell population decreases in miscarriage. These ndings lead to this
conclusion that dNK cells may do some roles in differentiation of
iTregs in decidua [74,75]. Both in vitro and in vivo ndings show
that cytotoxic activity, cytokine production and proliferation of NK
cells can be regulated by Treg cells [76,77]. TGF-b has also been
described as a factor capable of converting NK cells into dNK cells
[78] with high proliferation rates in vitro.
2.4. Interaction between Tregs and TH17
Pro-inammatory IL17-producing Th17 cells are a subset of Th
cells which are implicated in autoimmune as well as inammatory
diseases. There is an interest on the relationship between Th17 and
Treg cells [79]. It has been demonstrated that there is some degree
of plasticity between Tregs and Th17 cells, meaning that different
milieus can induce distinct cell subsets [80]. TGFb1 in the absence
of IL-6 simultaneously drives synthesis of both Foxp3 and the Th17
cell master switch, retinoic acid-related orphan receptor gt
(RORgt) [81]. Foxp3 then directly interacts with RORgt to repress
Th17 cell differentiation [82]. However, in the presence of IL-6,
Foxp3 expression is down-regulated, allowing RORgt to induce IL-
17 production and the conversion of naive T cells to Th17 cells [83].
Treg cells in the absence of adequate TGFb1 can convert
themselves into Th17 cells [84,85]. The ne balance between Treg
and Th17 cells is associated with maternal tolerance to the fetus
[86,87]. Any disturbances in this balance such as decrease in Treg
and/or increase in Th17 in humans can lead to gestational
problems, such as preterm birth (PTB) [88], recurrent pregnancy
loss (RPL) [51] or pre-eclampsia (PE) [89]. It is suggested that Treg
cells miss their suppressive activity in inammatory conditions
[90]. Tr1 cells might be crucial in controlling tissue inammation
through inhibiting Th17 cells in vivo in an IL-10-dependent manner
[91]. IL-27 has been reported to have immunoregulatory effects by
rendering both Foxp3+ and Foxp3
T CD4+ cells to produce IL-10,
thus promotes the differentiation of Tr1 cells and prevents Th17
development [92]. Expression of IL-27 has been observed in feto-
maternal interface both in humans and mice [93,94].
As mentioned above, TGFb is involved in induction and
maintenance of Treg in uterus and may be replaced for IL-2 in
this tissue. The other cell sources for TGFb in uterus are epithelial
cells and maternal lymphomyeloid cells including Th3-type
suppressor cells [95].
64 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173

2.5. Functional mechanisms of Tregs in normal pregnancy
Tr1 and Th3 suppressor T cells exert their suppressive effects via
release of immunosuppressive cytokines, such as IL-10 and TGFb
[96]. It seems that Tregs exert their suppressive function mainly in
a contact dependent manner [97100]. In mice, Tregs seem to
present cytokine-mediated suppression [101].
Immunosuppressive cytokines IL-10 and TGFb have been
shown to be released by Tregs thereby suppress the effector
lymphocytes [102]. It has been emerged that one important
mechanism in maternal tolerance to the fetus is tryptophan
breakdown by the enzyme IDO. DCs catabolize tryptophan, an
important nutrient for Tregs, by secreting IDO. A drop in
tryptophan amount leads to suppression of T cell responses.
Interestingly, CTLA-4 on Treg cells may affect the expression of IDO
[66,103105]. In human decidua CD4+CD25+ T cells have been
demonstrated to express high frequency of intracellular CTLA-4
[58]. Thus increase in Treg numbers may stimulate IDO expression
in APCs then diminish tryptophan concentration. It is possible that
only a certain DC subtype would be able to respond to CTLA-4 by
producing IDO, since CTLA-4Ig was not observed to elevate the IDO
mRNA expression in peripheral blood monocytes whereas
stimulation with IFNg clearly up-regulated the IDO mRNA levels
[58]. In addition, placental cells express CTLA-4, conrming
immunoregulatory role for CTLA-4 in uteroplacental interface
[106]. Decidual CD4+CD25high Treg cells express surface CTLA-4
while CD4+CD25high Tregs from peripheral blood lack the expres-
sion of CTLA-4 in human normal pregnancy [46]. In miscarriage
cases the expression of CTLA-4 on decidual CD4+CD25high Treg
cells is downregulated [46]. All these imply the possible role of
CTLA-4 molecule on Tregs in maintaining normal pregnancy.
However on the contrary, blocking CTLA-4 has revealed no
contribution on Treg suppressive activity in a pregnancy murine
model [107]. Therefore, the precise role of CTLA-4 in protective
effects of Tregs in pregnancy remains to be elucidated. Pro-
grammed death 1 (PD-1) and its ligand PDL-1 may also play
signicant role in tolerance to the fetus [108]. It has been observed
that blocking PDL1 in an animal model reduced regulatory function
and resulted in fetal death [109]. Loss of PDL1 function induces Th1
and Th17 proliferation, and disturbs Th1/Th2/Th17 balance, which

Table 1
The role of immune regulatory cells in normal pregnancy.

Immune Mechanism Role in pregnancy References

cells
Treg Secretion of IL-10 and TGF-b
Suppress effector lymphocytes Groux et al. [34]
Weiner [102]
Induction of IDO expression in DC by CTLA-4
Decrease in tryptophan level Munn et al. [104],
Melloret al. [103],
Fingeret al. [105],
Fallarino et al. [66]
PD1PDL1 interaction
inhibit Th1 and Th17 proliferation Habicht et al. [109],
Taglauer et al., [108]
DAddio et al. [110]
Up-regulation of galectin-1
Regulate T cell activation and cytokine production Rabinovich et al. [114], Dias-Baruf

Promote apoptosis of activated T cells et al. [115] Matarrese et al.[113]

Inhibit cell growth progression Ilarregui et al. [116]

Inducing tolerogenic DCs
Cell surface TGF-b1
Regulate T cell activation and NK cell function Nakamura et al. [118]
Increasing LIF and HO-1 levels
Implantation success Zenclussen et al. [15]

Up-regulate TGB-b, IL-10 and CTLA-4
Breg Production of IL-10
Keep DC in an immature state Fillatreau et al. [156]

Inhibit the production of TNF-a by T cells Schumacher et al. [160]
Rolle et al.[151]
Jensenet al. [146]
NKT Release of IFN-g and IL-4
Regulate the Th1/Th2 balance Tupin et al. [190]

Massive activation of NKT cells induces pregnancy loss Ito et al. [182]
Boyson et al. [199]
MDSC unknown
Suppression of the adaptive immunity by limiting the Zhao et al. [211]
proliferation and inltration of DCs and T cells
Secretion of ARG-1, iNOS and IDO and so depletion
Suppress T cell activation and function Rodriguez et al. [225]
of arginine, cysteine and tryptophan Condamineet al. [222]
Fletcher et al. [223]
Membrane-bound TGF-b
Inhibit T cell responses Li et al. [232]
Up-regulation of Cox2 unknown Zhao et al. [203]
unknown
Induce the proliferation and differentiation of Foxp3 + Treg Dilek et al. [233]
cells Schlecker et al. [234]
Expression of PD-L1, CD80/86, and galectin-9 unknown De Wilde et al. [236]
Noman et al.[237]
Down regulating the expression of L-selectin on T
Reduce homing to lymph nodes Hanson et al. [235]
cells
unknown
Express a predominant but not exclusive Th2-type prole Bartmann, et al. [207]
MCP-1 expression
Polarization of T cells into Th2 type Guet al. [239]

inhibit NK cells cytotoxicity Xu et al. [240]
Expression of chemokine TARC
Induce Th2 response Tsuda et al. [241]
Engert et al. [242]

Abbreviations: IDO: Indoleamine 2,3-dioxygenase, DC: Dendritic cell, CTLA-4: Cytotoxic T-lymphocyte-associated protein 4, PD-1: Programmed cell death protein 1, PDL-1:
Programmed death-ligand 1, TGFb1: Transforming growth factor beta 1, LIF: Leukemia inhibitory factor, HO-1: Heme oxygenase-1, TNFa: Tumor necrosis factor alpha, IFNg:
Interferon gamma, IL-4: interleukin 4, IL-10: interleukin 10, ARG-1: arginase-1, iNOS: inducible Nitric oxide synthase, COX-2: Cyclooxygenase-2, Foxp3: Forkhead box protein
P3, MCP-1: Monocyte chemoattractant protein-1, TARC: Thymus- and activation-regulated chemokine, MDSC: Myeloid-derived Suppressor Cell, Breg: regulatory B cell, Treg:
regulatory T cell, NKT: Natural killer T, Th1: T helper-1, Th2: T helper-2, Th17: T helper 17, NK: Natural killer.
 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173 65

lead to prevention of fetomaternal tolerance [110]. Studies in PD-1
knockout mice bearing allogeneic pregnancy showed increased
abortion rate, but the same rate was not observed in syngeneic
pregnancies [111] which supports the effects of PD-1 pathway in
fetomaternal tolerance. As shown in Table 1, Tregs up-regulate
immune regulatory molecule galectin 10 [112]. Galectin1 regulates
T cell activation and cytokine production [113,114], promotes
apoptosis of activated T cells and inhibits cell growth [112,113,115].
These ndings suggest galectin1 expressing Treg may play a role in
the maternal-fetal tolerance. Ilarregui et al. showed that DCs
exposed to galectin1 promote IL10-mediated immune tolerance
[116], which is critical in pregnancy. Galectin1-decient mice show
loss of allogenic pregnancies, supporting a role for galectin1 in
inducing tolerogenic DCs and also generating Tr1 cells in decidua
to maintain allogeneic fetus [117]. Cell surface TGF-b1 is one
contact-dependent mechanism for CD4+CD25+ Treg cells in order
to regulate T cell activation and NK cell function [118]. In a study
conducted on mice has been shown that the role for surface TGF-
b1 may be controversial since TGF-b1 knockout Treg cells could
exhibit suppressive function [119].
Treg transfer studies showed that Tregs create a microenviron-
ment rich in TGF-b, leukemia inhibitory factor (LIF) and Heme
oxygenase 1 (HO-1) at fetomaternal interface [120]. LIF is essential
for implantation success [121,122], however LIF participation in
elevating maternal tolerance to the embryo by affecting Th1/Th2
balance is less understood [2]. Although some evidences demon-
strate involvement of LIF in graft acceptance in mouse models
[123,124] suggesting that LIF may have roles in promotion of
tolerance. Intriguingly, transfer of Treg to prevent abortion in mice
is efcient only very early in pregnancy, before implantation occur
[125]. An augmentation in local levels of LIF following Treg transfer
in mice has indicated an importance of LIF in fetomaternal
tolerance induced by Tregs [120].
HO-1 is important in maternal-fetal tolerance. HO-1 level is low
in placental tissue in abortion-prone mice compared with normal
pregnant mice [125]. Foxp3+ Treg cells increase HO-1 level in
placenta [126] indicating the role of HO-1 in Treg-mediated
tolerance induction. HO-1 may act in a Treg-dependent manner,
since HO-1 induction could up-regulate TGB-b, IL-10 and CTLA-4
[127] and Treg marker neuropilin-1 [128]. These mechanisms are
shown in Fig. 1 in brief.
3. Regulatory gdT cells
T cells can be divided into two lineages based on the TCR
receptor chains, ab-TCR and gd-TCR expressing cells. The ab-T
cells comprise the bulk of the T cell population in the blood and
lymphoid tissues while a small portion are TCRgd cells. Unlike
ab-T cells, it seems that majority of gdT cells are generated in
extrathymic sites, only a portion of these cells are originated from
thymus [129].
The gdT cells are present in endometrium during pregnancy in
all mammals [130]. Study on murine system has revealed that the
frequency of uterine gdT cells in allogeneic pregnancy is higher
than syngeneic pregnancy and sex hormones have been shown to
affect gdTCR expression in the pregnant uterus [131]. The number
of gd T cells is increased in peripheral blood and decidua of healthy
pregnant women compared with that of non-pregnant ones [132].
Regarding the characteristics of decidual gdT cells, it is observed
that they are double negative granulated lymphocytes which
express neither CD4 nor CD8 [133]. They express CD69 (an
activation marker), CD45RO, CD94 (NK cell receptor) [133], NKG2D
and CTLA-4 and are also CD2-positive. Initial studies have

Fig. 1. Mechanisms of Treg in induction of fetomaternal tolerance. Tregs secrete IL-10 and TGFb and suppress effector lymphocytes. The interaction between CTLA-4 on Treg
and B7-ligand on DCs, makes DC to produce IDO which deprives T cells from Tryptophan. The crosstalk between dNK and CD14+ myelomonocytic cells results in IFNg
production that induces IDO expression in CD14+ cells. dNK cells release TGFb in fetomaternal interface. DCs, dNK and CD14+ cells through the secretion of TGF-b and IDO can
induce Treg differentiation. Tregs up-regulate immune regulatory molecule Galectin-1. Galectin-1 promotes apoptosis of activated T cells. DCs exposed with galectin-1
show IL-10 mediated immune tolerance. PD-1 is another regulatory molecule on Tregs. Loss of PDL1 function induces Th1 and Th17 proliferation. Tregs create a
microenvironment rich in LIF and HO-1. LIF is essential for implantation success. HO-1 is also important in fetomaternal tolerance.
Abbreviations: TGFB: Transforming growth factor beta, IL-10: Interleukin-10, PDL: Programmed death-ligand, PD-1: Programmed cell death protein 1, LIF: Leukemia
inhibitory factor, HO-1: Heme oxygenase-1, IFNg: Interferon gamma, IDO: Indoleamine 2,3-dioxygenase, CTLA-4: Cytotoxic T-lymphocyte-associated protein 4, Treg:
regulatory T cell, Beff: effector B, Th1: T helper1, Th17: T helper17, dNK: decidual Natural killer, dCD14+ cell: decidual CD14-positive cell, DC: Dendritic cell, Foxp3: Forkhead
box protein P3.
66 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173
suggested that gd T cells existing in uterus produce TGF-b and
suppress fetal rejection by maternal immune responses [134].
Further studies showed that decidual gd T cells produce IL-10 and
TGF-b at high levels, TNF-a and IFN-g at low levels and little or
none of IL-2 and IL-4 [132]. Lots of data from human and murine
system demonstrated that decidual gd T cells appear to contribute
to Th2 bias in maternal-fetal interface in favor of fetal tolerance
[132,135,136]. A population of gdT cells producing IL-10 and TGF-b
cytokines has been isolated from tumor-inltrating lymphocytes.
These gdT cells may be involved in inhibition of immune responses
to tumor [137]. Findings on IL-10/TGF-b dominant expression in
decidual gd T cells have led us to consider them as Treg cells.
Decidual gd T cells appeared to induce proliferation and invasion of
human rst trimester trophoblast via IL-10 secretion in Fans and
collegoues work [132], indicating that decidual gd T cells may play
an important role in placenta development and function in human.
It is currently unknown that by which mechanisms IL-10 can
promote trophoblast invasion and proliferation.
There are two populations of gdT cells, resident and circulating
gdT cells. The main difference between the resident and circulating
gd T cells is that they use different Vd chains. The resident gdT cells
are Vd1+ but the circulating part is Vd2+ [138]. Vd1+ gdT cells
reside in the epithelial surfaces of the intestine, tongue, lung,
uterus, vagina, and murine skin [138]. In healthy pregnant women,
there is a dominance of Vd1+ circulating cells, while women with
recurrent abortions have an accumulation of Vd2+ circulating cells.
Activated gdT cells are much more in women with normal
pregnancies than in recurrent aborters [139].
4. Bregs
Pregnancy is a unique condition in which the immune system of
mother meets a double challenge, to defend against microbial
agents and at the same time must tolerate the semiallogenic fetus
[140]. Cytokines produced by immune and nonimmune cells are
important players in controlling immune response [141]. IL-10 is a
suppressive anti-inammatory cytokine that correlates with
pregnancy outcome and could be used as a therapeutic way in
order to prevent naturally occurring pregnancy loss in a mouse
model [142]. However, IL-10 gene deletion could not induce
abortion [143145]. So, necessity of IL-10 in pregnancy success is
not clear [146]. It is accepted that trophoblasts or T cells are cellular
source of IL-10. Recently a new cell source of IL-10 has been
recognized which is known as regulatory B or B10 cells [147149].
Two main populations of B cells have been distinguished based on
cellular markers, function, and localization [150]. In the past, the
role of B cells in pregnancy was just attributed to antibody
production [151]. During normal pregnancies protective antibodies
are increased compared with non-pregnant females [152,153]. In
addition to antibody production, B cells have emerged as
regulators of immune responses [154]. B10 cells in particular are
potent immunoregulatory cell subtypes with ability to produce IL-
10 [147,149,155]. Indeed most of suppressive functions of
regulatory B cells are directly attributed to their capacity to
produce IL-10 [147,155157]. It has been suggested that IL-10-
producing B10 cells act to prevent autoimmunity [158] and are
important mediators of chronic infections [159].
Jensen et al.showed that the frequency of regulatory B10 cells
was signicantly higher than that observed in nonpregnant CBA/J
female mice, but AP (Abnormal Pregnant) mice did not show high
levels of CD19+CD5+CD1d+ regulatory B10 cells, in fact percentage
of B10 cells in these animals was comparable with nonpregnant
females. Then, they examined IL-10 levels in the spleen of
nonpregnant, NP (Normal Pregnant) and AP female mice. IL-10
mRNA level in the spleen of normal pregnant mice was up-
regulated compared with nonpregnant mice, but that was not
observed in AP animals. They observed that in addition to
augmentation in frequency of regulatory B10 cells in normal
pregnancies, their ability to produce IL-10 mRNA is also increased.
They transferred regulatory B10 cells to AP female mice and
observed that adoptive transfer of regulatory B10 cells impedes
immunological abortions [146]. Thus, the transfer of regulatory
B10 cells into AP animals normalizes the abortion rate, which is
related to Treg expansion and keeping DCs in an immature state
[146,160]. Jensen et al. demonstrated that IL-10 produced by
regulatory B10 cells is fundamental for keeping DCs in an
immature state during normal pregnancy. IL-10 prevents mono-
cytic DCs to develop into IL-12 producing mature DCs, thereby
inhibits them to activate T cells and to induce Th1 differentiation
[161]. Rolle et al. observed signicantly augmented frequencies of
CD19+CD24hiCD27+ Breg in normal pregnant compared to non-
pregnant women. Women suffering from miscarriages showed
signicantly lower percentages of CD19+CD24hiCD27+ Breg than
women with normal pregnancies at the rst trimester. In addition,
they found that almost all CD19+CD24hiCD27+ cells (95%)
expressed the receptor for hCG. Interestingly, isolated CD19+ B
cells were able to produce IL-10 in response to human recombinant
hCG, in vitro. Thus hCG induces IL-10 secretion by B cells and in this
way inuences the tolerance exerted by Bregs [151]. A clinical
observation in regard to the association between reproductive
hormones and regulatory B cells is the remission experienced by
women suffering MS during pregnancy [162]. Subramanian et al.
showed that regulatory B cells are involved in the E2-mediated
protection of EAE in mice lacking Tregs [163]. This study supports
the notion that sex hormones have a positive effect on the activity
of regulatory B cells leading to protection against disease. These
results are consistent with former reports demonstrating the role
of regulatory B cells in protection against EAE through secretion of
IL-10 [156,164,165]. B lymphocytes express ER-a
receptor for
Eastrogen- signaling by this receptor is involved in the develop-
ment, survival, expansion, and maturation of these cells [166168].
Progesterone (P4) has also been reported to affect immunoregula-
tion by B cells [169,170]. It is reported that administration of P4
ameliorates the severity of EAE through elevating the numbers of
CD19+ cells and level of IL-10 [171].
Recurrent spontaneous abortion is associated with elevated
level of pro-inammatory cytokine TNFa and blocking of TNFa
was suggested as a treatment for recurrent spontaneous abortion
[172]. Regulatory B10 cells inhibit secretion of TNFa by activated T
cells in several pathological situations [173]. Isolated CD19+ B cells
from pregnant women stimulated with CD40L/CpG and secreting
IL-10 were reported to inhibit TNFa production by activated CD4+
T cells [151]. Interestingly, B cells isolated from pregnant women
without activation with CD40L/CpG exerted the same effect. In
contrast, CD40L/CpG activated and even non-activated B cells were
not able to inhibit TNFa secretion by T cells [151], suggesting these
cells in pregnant women are activated naturally to produce IL-10,
perhaps with a soluble factor, to apply immunomodulation effects.
5. NKT cells
Natural killer T (NKT) cells constitute a distinct subgroup of
lymphocytes expressing both T-cell and NK-cell markers. These
cells are subdivided into two subgroups including: type I or
invariant NKT (iNKT) cells with highly restricted TCR (V a24-J a18,
V b11) and type II that is a population of CD1d-restricted NKT cells
that express diverse TCRs, referred to as non-invariant NKT (non-
iNKT) cells [174]. In addition, a third group named NKT-like cells
that resembles NKT cells has been recently described. In contrast to
traditional NKT cells, NKT-like cells (CD3+CD56+, CD3+CD16+)
are restricted to MHC but not CD1d [175]. NKT-like cells regulate
both innate and adaptive immune systems [176,177] and serve as a
 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173
bridge between the two systems [178]. They can modulate the Th1
and Th2 balance [179,180]. NKT cells have been found in both
mouse and human decidua [181183] and affect maternal-fetal
tolerance and successful implantation [184186]. Ito et al. reported
that NKT cells were present in decidual tissues of pregnant mice
and induced abortion when stimulated by a specic ligand for
Va14, aGalCer [182]. Tsuda et al. reported more NKT cells
accumulated in the human decidua compared with murine
decidua [183]. NKT cells are not present in the endometrium
during the nonpregnant period [182], but the number of NKT cells
in the decidua is apparently increased during early pregnancy
[181,183] and then declines during the late trimester of pregnancy
[187].
NKT-like cells were also found in the decidua, and were
substantially increased in the URSA (unexplained RSA) group than
in the early pregnancy and nonpregnant groups in peripheral blood
(PB) and decidua [188]. Activation of NKT cells has been observed
in pregnancy loss. Heuvel et al. reported that high frequency of NKT
cells in PB correlates with recurrent pregnancy loss or implanta-
tion failure [189].
NKT cells modulate adaptive immune system by affecting the
Th1/Th2 balance, in vivo [190]. NKT cells rapidly secrete IFN-g and
IL-4 after activation, thereby regulate Th1/Th2 polarity [191]. IFN-g
released by NKT cells can cause activation of other cell types such
as NK cells in decidua, causing NK cell cytotoxicity and cytokine
production [192]. The iNKT cells can activate other immune cells,
such as DCs, macrophages, neutrophils, B cells and T cells by
releasing cytokines [193]. Contact dependent mechanisms be-
tween NKT cells and trophoblasts are also implicated in inducing
abortion [182]. The change in NKT cells may disturb Th1/Th2
balance and leads to abortion. In supporting the role of NKT-like
cells during implantation, Miko et al.demonstrated that changes of
NK and NKT-like cells phenotype during the implantation and early
pregnancy in the same individual may also be important for
successful embryo implantation [184]. Non-iNKT cells have been
described in the bone marrow and hepatitis C virus-infected liver
in humans [194,195]. Organ specic context might dictate
functional capabilities of resident non-iNKT cells, since non-iNKT
cells residing the bone marrow are Th2 like whereas those present
in infected liver are Th1-biased. Although the iNKT cells present in
the decidua affect the maintenance of pregnancy in both mice and
humans [181,196], the role of non-iNKT cells in pregnancy remains
unknown. Uemura et al. observed that one subclass of CD1d
restricted NKT cells that is distinct from the Va24 iNKT cells resides
in the decidual tissue and is capable to retain a Th2 environment
during pregnancy. According to their reports, non-iNKT cells
accumulated in the decidua may interact with the trophoblasts
that express CD1d molecules, having important functions in
pregnancy [185]. Although the decidual non-iNKT cells express
diverse TCRs, they do not recognize fetal alloantigens. This
suggests that their recruitment to the decidua might be through
interaction with CD1d on trophoblasts rather than recognition of
fetal alloantigens. Pregnancy-associated hormones such as estro-
gen and progesterone may have various effects on these cells [197].
Decidual and peripheral iNKT cells differ in IFN-g and IL-4
production. The iNKT clones in decidua showed a bias toward IFN-
g secretion, while peripheral blood CD4+ iNKT population favors to
release IL-4. These ndings are consistent with the previous study
by Takahashi et al. [198]. RT-PCR results from mouse decidual iNKT
cells indicated the same results [182], proposing Th1-biased iNKT
cells participate in both species. Boyson and colleagues demon-
strated that activation of iNKT cells leads to both early pregnancy
loss and preterm birth, so mechanisms operating in early gestation
are different from late stages of pregnancy [199]. Recently, Li et al.
identied the molecular mechanisms concerning the role of iNKT
67
cell activation in inammation induced preterm birth in a mouse
model [200,201].
6. MDSCs in pregnancy
MDSCs are a heterogeneous cell population consisting of
immature granulocytes, macrophages, and DCs, which are the
intermediates of the normal myeloid development in bone marrow
[202]. They are characterized with myeloid origin, immature state,
T cell suppression [203] and lacking markers of mature myeloid
and lymphoid cells [204]. In the noemal condition, immature
myeloid cells differentiate into macrophages, DCs, and granulo-
cytes and are scarcely seen in peripheral blood. But differentiation
in myeloid lineage is altered in some pathologies, in particular
malignancies and chronic infection and increased numbers of
immature myeloid cells are detected in circulation [205].
In mice, these myeloid cells are distinguished by co-expression
of two surface markers CD11b and Gr-1 (Ly6G/Ly6C) and are
subdivided into two groups including granulocytic MDSCs (G-
MDSCs) dened as CD11b+LY6G+LY6Clow cells and monocytic (M-
MDSCs) with CD11b+LY6G
LY6Chigh phenotype [206]. In humans,
very heterogeneous phenotypes of MDSC are described [207].
Recently, two human MDSCs have been reported including
CD14
CD15+CD66b+ (granulocyte, G-MDSCs) and
CD14CD15low/
(monocyte, M-MDSCs) [208,209]. MDSCs have
been detected in uteri and placentas of mice [210,211]. More
recently, MDSCs have been identied in human gestation. In
peripheral blood of pregnant woman, MDSCs appear to play an
important role [212,213]. Studies that show progesterone increases
MDSC also conrmed the importance of MDSC during pregnancy in
mice [214]. Other observations indicate that the presence of
maternal MDSC is related to the more metastatic activity and
greater aggression of some tumors such as breast cancer, cervical
cancer, lymphomas, malignant melanoma, and leukemias during
pregnancy [211].
An experiment to investigate the role of MDSCs in immune
ontogeny revealed that granulocytic MDSCs are present in the large
numbers in pregnant women and in cord blood and drop rapidly
during infancy [205]. Kostlin et al. demonstrated that G-MDSCs,
but not M-MDSCs, are increased in the peripheral blood of
pregnant women. They observed that percentages of G-MDSCs
were elevated in the 1st, 2nd, and 3rd trimester compared with
nonpregnant controls and there was no signicant differences
between these three trimesters [212]. On the other hand, Nair et al.
observed that percentage of CD33+ CD11b+ cells were at highest
level during the 1st trimester of pregnancy then decreased
signicantly in 3rd trimester [213]. After delivery, the number of
G-MDSCs decreased within a few days to levels of nonpregnant
controls [212]. Moreover, percentage of M-MDSCs did not change
signicantly during pregnancy [212], while Pan and colleagues
observed that the population of M-MDSCs was elevated signi-
cantly in pregnant women compared with healthy donors and
postpartum women. Interestingly, the proportion of M-MDSCs
were raised throughout the rst to the second trimesters and
declined from the third trimester, indicating dynamics of MDSCs
during gestation. The differences observed from these two studies
may be due to the genetic background of subjects or cytokine
milieus produced in the individuals or for other unknown reasons
[215].
Nair et al. found that functionally suppressive MDSCs decrease
in blood and endometrium of miscarriage subjects compared with
control women undergoing successful pregnancies, especially in
the rst trimester [213].
MDSCs do not need to be present in the large numbers to exert
their suppressive functions as it has been previously shown that
68 M. Ghaebi et al. / Biomedicine & Pharmacotherapy 88 (2017) 6173
only 3% of MDSCs are required to completely block T cell
proliferation, in vitro [216,217].
Pan et al. also showed further immunosuppressive effects of
oestrogen. They reported oestrogen facilitates the expansion and
activation of M-MDSCs in human pregnancy [215].
All MDSCs are characteristically immunosuppressive and
function via suppression of T cells and/or NK cells [218,219].
MDSCs isolated from early septic mice produce proinammatory
cytokines TNF-a, IL-6, and IL-12 while MDSCs derived from late
septic mice produce TGF-b and IL-10 and were immunosuppres-
sive [220,221]. The context-specic functions of these MDSCs led
to speculation that in the feto-maternal interface, the phenotype
and activity of MDSCs depend on gestation time and the maternal
environment [203]. In the study conducted by Zhao et al. pregnant
mice were recently treated with Gr-1 antibody to deplete MDSCs or
a low dose of LPS to transform MDSCs into activated neutrophils,
signicant increases in uterine DCs and T cells were observed,
indicating that MDSCs may mediate the suppression of the
adaptive immunity in the fetoplacental environment by inhibiting
proliferation and inltration of DCs and T cells, in vivo [211]. MDSCs
suppress T cell activation and function through secretion of
arginase-1 (ARG-1), nitric oxide synthase (iNOS) and indoleamine
2,3dioxygenase (IDO) in order to deplete essential nutrients for T
cell proliferation, l-arginine (l-Arg), l-cysteine and tryptophan
[222224]. T cells deprivation from l-Arg hinders proliferation by
reducing CD3z-chain expression, preventing the expression of cell-
cycle regulators cyclinD3 and cdk4 and impairing the production of
cytokines such as IFN-g [225]. Production of peroxynitrite (PNT) to
nitrosylation of T cell receptors via reactive oxygen species (ROS)
and iNOS is another mechanism of MDSC [222]. PNT could cause
nitration of the T cell receptor-CD8 complex that hinders binding to
MHC class I and makes T cells unresponsive to stimulation by
antigen [203]. NO seems to be essential for successful implantation
[226], and a link between early pregnancy loss and production of
NO by decidual macrophages was assumed [227]. Bartmann et al.
results suggest decidua iNOS expression in CD33+ cells is of
importance in early pregnancy, while in later pregnancy, CD33+
cells likely lose the expression of this enzyme [207]. The iNOS
secreted by MDSCs causes conversion of l-arginine to citrulline and
NO, which represses T cell action through inhibition of Jak/STAT
signaling, reducing MHC class II expression and inducing T cell
apoptosis [228231]. MDSCs can also inhibit T cell responses
through membrane-bound TGF-b [232]. Up-regulation of cyclo-
oxygenase 2 (cox2) is another mechanism of MDSC in fetomaternal
immune crosstalk [203]. MDSCs are involved in inducing
proliferation and differentiation of Foxp3+ Treg cells [233,234].
In addition, MDSCs downregulate the expression of L-selectin on T
cells, which results in a reduced homing to lymph nodes and
tumors [235]. Additional mechanisms include expression of
program death ligand 1(PD-L1), CD80/86, and galectin-9
[236,237]. In Bartmann et al. study, decidual CD33+ cells did
express a predominant but not exclusive Th2-type prole.
Interestingly, MCP-1 was expressed by all CD33+ cells investigated
herein [207]. Beside its chemoattractant inuence on monocytes,
macrophages and lymphocytes [238], MCP-1 is linked with Th2
response in T-cell immunity [239]. Moreover, MCP-1 inhibits
perforin production in uterine NK cells [240]. Therefore, decidual
MDSCs not only suppress T cell proliferation but also contribute to
polarization of T cells into Th2 type immunity and inhibit NK cells
cytotoxicity. These functions all together promote a successful
pregnancy. Another chemokine, TARC, which operates in favor of
Th2 cell responses in the decidua [241] is expressed by the CD33+
cells and not by the CD14+ cells [242] and conrms the role of the
CD33+ decidual MDSCs in assisting maternal immune environ-
ment to maintain pregnancy.
7. Conclusion
Pregnancy is an active immunological process and leukocytes
play an important role in gestation. Regulatory cells are present in
fetomaternal interface and they have demonstrated to be potently
immunosuppressive during pregnancy and in some cases of
reproductive disturbances their function and/or number are
altered. These ndings suggest that they may be benecial in
therapeutic approaches to pregnancy associated disorders. How-
ever many experiments have been conducted to investigate and
clarify the role of different immune cell types in successful and
disturbed pregnancies, the exact mechanisms of their function and
precise role remain to be elucidated.
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