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Regulatory T Cells: Regulators of LifeAnne Schumacher, Ana Claudia Zenclussen
Department of Experimental Obstetrics & Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
Keywords
Autoimmune disease, infection, pregnancy,
tolerance, Treg
Correspondence
Ana Claudia Zenclussen, Experimental
Obstetrics and Gynecology, Medical Faculty,
Otto-von-Guericke University, Gerhart-
Hauptmann-Straße 35, 39108 Magdeburg,
Germany.
E-mail: [email protected]
Submission January 30, 2014;
accepted February 25, 2014.
Citation
Schumacher A, Zenclussen AC. Regulatory T
cells: regulators of life. Am J Reprod Immunol
2014; 72: 158–170
doi:10.1111/aji.12238
Pregnancy still represents one of the most fascinating paradoxical phe-
nomena in science. Immediately after conception, the maternal immune
system is challenged by the presence of foreign paternal antigens in the
semen. This triggers mechanisms of recognition and tolerance that all
together allow the embryo to implant and later the fetus to develop.
Tolerance mechanisms to maintain pregnancy are of special interest as
they defy the classical immunology rules. Several cell types, soluble fac-
tors, and immune regulatory molecules have been proposed to contrib-
ute to fetal tolerance. Within these, regulatory T cells (Treg) are one of
the most studied immune cell populations lately. They are reportedly
involved in fetal acceptance. Here, we summarize several aspects of Treg
biology in normal and pathologic pregnancies focusing on Treg frequen-
cies, subtypes, antigen specificity, and activity as well as on factors influ-
encing Treg generation, recruitment, and function. This review also
highlights the contribution of fetal Treg in tolerance induction and
addresses the role of Treg in autoimmune diseases and infections during
gestation. Finally, the potential of Treg as a predictive marker for the
success of assisted reproductive techniques and for therapeutic interven-
tions is discussed.
Introduction
The nomenclature of regulatory T cells (Treg) was
first brought into light by Sakaguchi et al. in 1995,
although already in the 70s, the existence of ‘sup-
pressor T cells’ with regulatory properties was pro-
posed.1 Nowadays, this specialized T-cell
subpopulation is best known for their function in
suppressing autoreactive and alloreactive immune
responses, thereby preventing autoimmune diseases
and allograft rejection.2 Additionally, a crucial role
for these cells in the establishment and maintenance
of fetal tolerance has widely been reported in both
humans and mice.3–6 CD4+CD25+Foxp3+ Treg can be
either generated in the thymus as naturally occur-
ring Treg (nTreg) or in the periphery after encounter
of antigens as induced Treg (iTreg). iTreg can be fur-
ther subdivided into CD4+ T-cell subsets such as type
1 regulatory cells (Tr1), T-helper 3 cells (Th3), and
CD25+ Treg. Whereas Tr1 cells mainly produce IL-
10, TGF-b is the major cytokine of Th3 cells. Both
cytokines are fundamental for the function of each
Treg subtype.7,8 CD4+CD25+ Treg express surface
markers such as the alpha chain of the IL-2 receptor
CD25,2 CD127 (human only),9 glucocorticoid-
induced tumor necrosis factor receptor-related pro-
tein (GITR),10 cytotoxic T lymphocyte-associated
antigen 4 (CTLA-4)11, and a unique intracellular
marker, X-linked Forkhead box P3 (Foxp3) validated
as the ‘master switch’ for Treg development.12
Regulatory T cells in human and murine pregnancy
Origin and Generation
Thymus-derived Treg as well as peripherally induced
Treg seem to be involved in immune regulatory pro-
cesses toward fetal alloantigens.13,14 The peripheral
Treg pool is suggested to be maintained by a contin-
uous conversion of na€ıve T cells into Treg in the
presence of TGF-b15 or through T-cell stimulation by
suboptimal activated dendritic cells.16 Additionally,
American Journal of Reproductive Immunology 72 (2014) 158–170
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molecules directly produced at the fetal–maternal
interface, such as the heme-degrading enzyme heme
oxygenase-1, may be involved in Treg generation.17
Recently, Samstein et al. proposed a conserved non-
coding sequence 1 (CNS1)-dependent mechanism of
extrathymic Treg differentiation that emerged in pla-
cental animals and enforce fetal–maternal tolerance.
In detail, the authors demonstrated that the Foxp3
enhancer CNS1 is essential for peripheral Treg but
dispensable for thymic Treg generation. Interestingly,
they proved that allogeneically paired CNS-1-defi-
cient females show slightly increased fetal resorption
rates,13 suggesting a role for peripheral Treg in fetal
tolerance induction. In agreement, we lately con-
firmed the existence of an extrathymic Treg popula-
tion at later pregnancy stages. Moreover, we found
an accumulation of thymus-derived Helios+ Treg in
thymus and draining lymph nodes at early preg-
nancy suggesting that Treg, predominantly of thymic
origin, are needed for pregnancy establishment.14
Kinetics of Treg during the reproductive cycle and
pregnancy
Treg frequency fluctuates during the human men-
strual cycle as well as during the murine estrus
cycle. In both reproductive cycles, Treg increase in
number every time a female becomes receptive and
decline afterward.18–20 This fluctuation of Treg dur-
ing the reproductive cycle is proposed to be hor-
mone driven.21
In human pregnancy, most studies observed a
Treg augmentation during the first and second tri-
mester in peripheral blood5,22 being this augmenta-
tion even more pronounced in decidual tissue.23 By
contrast, Mj€osberg et al.24 found diminished levels of
CD4+CD25high Treg in the second trimester and sug-
gested an re-evaluation of Treg frequencies during
pregnancy. In the third trimester, Treg levels start to
decrease25 and further decline with successive stages
of labor.26 These Treg changes may be related to a
brief activation of maternal immune system as labor
begins.27 Moreover, the suppressive activity of Treg
is decreased in term labor and preterm labor (PL)
suggesting that the change of Treg function
toward suppression may initiate labor. A distinct
subset of Foxp3+DR+ Treg among the total
CD4+CD127lowCD25+ Treg pool has been reported to
be critically involved in PL induction.28 In normal
pregnant mice, we observed an initial Treg augmen-
tation as early as day 2 of pregnancy, and then, Treg
decreased at implantation time and again raised on
day 10 of pregnancy.14,29
Treg Subtypes
The majority of studies evaluating Treg number and
functionality during normal and pathologic pregnan-
cies define Treg as CD4+CD25highFoxp3+ cells in
humans or as CD4+CD25+Foxp3+ cells in mice. How-
ever, some studies focus on Treg subtypes within the
so-called Treg population. In this regard, Andrea
Steinborn et al. evaluated the number of different
Treg subtypes within the total Treg pool during nor-
mal and pathologic pregnancies. The authors
observed between the 10th and 20th weeks of gesta-
tion a clear decrease in the percentage of DRhigh
CD45RA� and DRlow CD45RA� Treg and a clear
increase in the percentage of naive DR� CD45RA+
Treg. Compared with healthy pregnancies, the fre-
quency of naive DR� CD45RA+ Treg was signifi-
cantly reduced in the presence of pre-eclampsia (PE)
and after the onset of PL. Interestingly, they found
that the percentage of DRhigh CD45RA� and DRlow
CD45RA� Treg was increased significantly in preg-
nancies affected by PE, while PL was accompanied
by a significantly increased percentage of DRhigh
CD45RA� and DRlow CD45RA� Treg. The suppres-
sive activity of the total Treg pool was diminished in
both patient collectives. The authors suggest that PE
and PL are characterized by homeostatic changes in
the composition of the total Treg pool with distinct
Treg subsets that were accompanied by a significant
decrease in its suppressive activity.30 Additionally,
there are reports clearly identifying CD8+ T cells in
peripheral blood and decidual tissue with unique
regulatory properties and were suggested to be
involved in fetal tolerance.23,31,32 In addition, CD4�
CD8� gamma delta T cells with regulatory properties
have been also reported to function as immune reg-
ulators during pregnancy.33
Antigen Specificity
In 1953, Sir Peter Medawar hypothesized that the
recognition of foreign fetal antigens by maternal
immune cells is hampered by the placenta. He pro-
posed the placenta as a physiological barrier that
strictly separates fetal from maternal tissues. Half a
century later, the discovery of a bidirectional cell
transfer between the mother and her unborn child
revealed this hypothesis as not entirely true.
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Moreover, nowadays, there is a general consent that
the recognition of fetal antigens by maternal
immune cells is a necessary step that leads to an
active suppression of alloreactive maternal immune
responses and constitutes thereby the initial step of
fetal tolerance induction. Transplacental fetal–mater-
nal cell exchange has been proven to occur in both
species, human and mice.34–37 Tilburgs et al.38 nicely
showed that decidual T cells directly recognize fetal
HLA-C antigens and that this is associated with
increased Treg levels and diminished CD4+CD25dim
T-cell levels. In agreement with this observation,
there is a growing body of evidence that the recogni-
tion of foreign paternal/fetal alloantigens by Treg is
critically for their development and function.39–43
The first encounter of paternal alloantigens with
maternal immune cells, for example, antigen-pre-
senting cells (APCs), is supposed to take place imme-
diately after conception in vaginal lumen where
immune cells get in contact with paternal antigens
present in seminal fluid. These antigens can be pre-
sented by direct or indirect antigen-presenting path-
ways.44,45 Both seminal fluid and sperms have been
shown to foster Treg induction, expansion, and
immune regulatory activity.20,46–49 Furthermore,
TGF-b present in high amounts in seminal fluid may
contribute to Treg expansion.50 This early Treg
expansion may induce tolerance to paternal antigens
facilitating embryo implantation and fetal accep-
tance.
After implantation, the Treg pool is then further
maintained by the continuous release of fetal anti-
gens from the placenta guaranteeing fetal survival
until birth. Interestingly, post-partum fetal-specific
Treg may persist in the mother creating a memory
to paternal antigens51 and rapidly re-accumulate
during subsequent pregnancies.52
Treg Recruitment into the Fetal–Maternal Interface
Treg recruitment from the periphery into the fetal–maternal interface was proposed as an additional
pathway for local Treg accumulation.53–55 Here,
cytokines, chemokines, and hormones may serve as
attractors for a selective Treg migration into the
uterus. Cytokines and chemokine ligands such as
IL-8, MCP-1/3, RANTES, fractalkine, MIP-1a/b,IP-10, SLC, and CCL22 are widely expressed in uter-
ine tissue56,57, and the appropriate receptors CCR1,
CCR2, CCR5, CCR7, CXCR3, CX3CR1 have been
proven on T cells.58 We recently demonstrated that
mice genetically deficient for the homing receptor
CCR7 had diminished Treg numbers in the uterus.
Mating of these mice with syngeneic or allogeneic
males resulted in impaired implantation, even
though some animals did get implanted. Thus, CCR7
is partially involved in the homing of Treg to the
uterus.20 A study by Lin et al.59 revealed that
CXCL12 is dominantly expressed in trophoblast cells,
while its specific receptor CXCR4 is expressed on
Treg suggesting that CXCL12 can cause CXCR4+ Treg
migrating in the pregnant uterus. In a transplanta-
tion setting, Lee et al.60 showed that migration of
CCR4+ Treg in response to CCL22 was necessary to
promote tolerance toward the allograft. But not only
chemokines and their receptors are involved in the
mobilization of Treg to the uterus. Upon pregnancy
establishment, hormones dictate Treg migration into
the fetal–maternal interface. In particular, human
chorionic gonadotropin (hCG), the pregnancy hor-
mone per se, is of vital importance for Treg migration
and functionality. We confirmed the presence of the
luteinizing hormone/chorionic gonadotropin (LH/
CG) receptor on human and murine Treg and
showed an active Treg migration along a hormonal
gradient continuously maintained by human or
murine trophoblast cells that produce hCG or LH,
respectively.54,61,62
Normal Pregnancy versus Pathologic Pregnancy
Evidence for the relevance of Treg during pregnancy
can be derived from the finding by Andersen et al.63
who showed that a co-evolutionary process has
taken place between Foxp3 and the placenta. More-
over, since the first Treg pregnancy papers by Aluvi-
hare et al. as well as Heikkinen et al., both in
2004,3,5 several reports confirmed a fundamental
role of Treg for pregnancy success. In both, humans
and mice Treg have been shown to increase during
normal pregnancy and being diminished in their
number and activity in spontaneous abortion
cases.3–5,64–71 Consistently, Winger and Reed72 pro-
posed Treg as a superior pregnancy marker for
assessing miscarriage risk in newly pregnant women.
It is suggested that the impaired Treg augmentation
in patients suffering from recurrent spontaneous
abortions (RSA) is associated with an alteration in
the IL-6 trans-signaling pathway.73 Moreover,
diminished Treg numbers in unexplained RSA
(URSA) patients are accompanied with an increased
number of pro-inflammatory Th17 cells in peripheral
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blood and decidua. As suggested by the authors, the
balance between Th17 cells and Treg may be critical
to pregnancy outcomes.74 An impairment in Treg
augmentation is not only limited to RSA patients,
but can also be observed in patients suffering from
extra-uterine pregnancies54 or endometriosis.75
Interestingly, in the presence of hydatidiform moles,
decidual Foxp3+ Treg infiltration seems to be higher
compared to normal pregnancy.76 In PE patients,
Treg seem to be reduced in number and function,
while Th17 frequencies are elevated. Several studies
suggested a dysregulation of immune responses and
a shift to a more Th17-dominated inflammatory
response characteristic for this pregnancy disor-
der,77–84 while two studies were not able not find a
Treg alteration in PE patients.85,86 Hsu et al.87 pro-
posed that a special subtype of decidual CD14+DC-
SIGN+ APCs may play an important role in Treg
induction in healthy pregnancy and this is defective
in PE. In addition, an altered apoptosis signaling in
Treg might be associated with PE.88 All together,
these results clearly indicate the need for fully func-
tional Treg to ensure successful pregnancy.
Relevance of Treg at Different Pregnancy Stages
Although pregnancy complications have been associ-
ated with reduced Treg number and functionality, it
is still not defined whether Treg are absolutely
required at all pregnancy stages. Recent findings
suggest that Treg are critically involved in the estab-
lishment of fetal tolerance rather than in its mainte-
nance. Depleting Treg in two Foxp3.DTR-based
models prior to pairing drastically impaired implan-
tation. Treg deficiency before mating led to infiltra-
tion of activated effector T cells as well as to uterine
inflammation and fibrosis that later resulted in
reduced implantation success in both allogeneic and
syngeneic mating combinations.20 This suggests that
the presence of Treg in the uterus contributes to a
‘friendly’ microenvironment that will later facilitate
the implantation of the embryo, while their absence
converts the uterus in a hostile environment for
pregnancy to establish. This is consistent with obser-
vations carried out in infectious pathologies associ-
ated with infertility and worthy of further studies. In
an older study, Shima et al. depleted CD25+ cells by
injection of an anti-CD25 monoclonal antibody at
different pregnancy days. Based on their findings,
they concluded that Treg are important for the
implantation phase and tolerance during the early
stage of pregnancy, but might not be necessary for
maintenance of the late stage of allogeneic preg-
nancy.89
Mouse models to study Treg during pregnancy
One of the most prominent mouse models used to
study immune regulation during normal and patho-
logic pregnancies is the abortion-prone model first
described in 1980 by Clark et al.90 Abortion-prone
females show an impaired ability to increase their
peripheral and local Treg number as compared to
normal pregnant controls. A direct transfer of
Treg4,91 or the administration of substances provok-
ing Treg recruitment or expansion was successful in
preventing fetal resorption in abortion-prone
females as we and others showed.50,61,92–96 This
confirms the indispensability of Treg in this mouse
model. Furthermore, using models of selective and
transient ablation of cell populations (specifically
two Foxp3.DTR-based transgenic mouse models),
we could show that Treg ablation drastically impairs
the implantation process.20 In another transgenic
mouse model, D0Addio et al.97 showed that PDL-1
blockage resulted in diminished Treg numbers lead-
ing to increased embryo resorption and reduced lit-
ter size. In addition to these animal models where
Treg diminution can directly be correlated with
pregnancy success, other transgenic mouse models
may facilitate characterization of Treg in pregnancy.
Foxp3GFP animals previously described by Fontenot
et al.12 provide a good tool to easily localize Treg in
different organs, also in vivo by means of 2-photon
in vivo microscopy.20,61 Moreover, Treg induction
from CD4+Foxp3� T cells by Foxp3 upregulation
can be detected in recipient mice after adoptive
transfer of non-Treg by determining GFP expres-
sion.13,14
Hormonal influence of Treg function
Already, during the menstrual/estrus cycle and later
during pregnancy, hormones undergo profound
changes in their levels. The most prominent preg-
nancy-associated hormones are hCG, progesterone
(P4) and estrogen (E2). All three hormones have
been reported to influence Treg generation, migra-
tion, expansion and suppressive function. In the
last years, we focused our work on the highly
homologous hormones hCG and luteinizing hor-
mone (LH) and its influence on Treg. Both human
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and murine Treg express the LH/CG receptor.54,61
Direct interactions between the hormones and their
receptor expressed on T cells had been shown
already in the 80s.98 We were able to prove that
hCG not only attracts Treg to trophoblast cells but
also positively influences Treg number and suppres-
sive activity contributing to fetal tolerance. More-
over, hCG retains DCs in a immature, and thus,
tolerogenic state supporting Treg induction via an
indirect pathway.61 Very recently, we showed that
LH similar to hCG modulates Treg and DCs suggest-
ing that both hormones are key players in regulat-
ing adaptive immune responses during pregnancy
(accepted for publication). In agreement with our
data, Shirshev et al. nicely showed that the addition
of hCG to human PBMCs significantly increased the
number of Treg. The same authors found similar
effects of E2 on Treg augmentation but could not
prove any statistically significant effect of P4 on
Treg.99 Other research groups confirmed a positive
effect of E2 on Treg induction, expansion and func-
tion,22,100–104 while data addressing a P4 impact on
Treg remain controversial. Holdstock et al. as well
as Mao et al. provide evidence that P4 positively
influences the proportion and function of
Treg.105,106 By contrast, Mj€osberg et al.24 found a
Treg reduction after P4 treatment. Interestingly, Lee
et al.107 showed that P4 drives allogeneic activa-
tion-induced differentiation of na€ıve T cells from
cord blood, but not from adult peripheral blood,
into Treg.
Mechanisms of immune regulation by Treg
Treg are central players in immune regulatory pro-
cesses and reportedly interact with every other
immune cell type regulating their number and activ-
ity. For instance, Treg suppress the proliferation and
cytokine production of CD4+ and CD8+ T cells108,109
and inhibit the cytotoxicity of NK cells.110 In addi-
tion, Treg dampen the proliferation of B cells and
their immunoglobulin production111 and act as effi-
cient suppressors of DCs and macrophages.112–114
These immune regulatory properties of Treg seem to
be executed mostly in a contact-dependent fashion
and potentiated by the action of IL-10, TGF-b and
CTLA-4.115–117 Recently, it has been suggested that
IL-9 expression by Treg recruit and activate immu-
nosuppressive mast cells.118,119 However, despite
this broad knowledge about immune regulatory
properties of Treg, little is known about the precise
mechanisms how Treg contribute to fetal tolerance.
In a murine model of disturbed fetal tolerance, it has
been suggested that Treg mediate their protective
function through PD-1, IL-10 and HO-1 rather than
through CTLA-4 and TGF-b.41,120,121 By contrast, in
a human study, Jin et al.67 proposed a role for
CTLA-4 in Treg function. Here, CTLA-4 expressed by
Treg may interact with B7 molecules on DCs and
monocytes enhancing IDO activity in those cells by
induction of IFN-c.122 IDO itself has been reported
to support fetal acceptance by suppressing T cell
activity.123 Moreover, we recently suggested an
important regulatory function for Treg in the pre-
implantation period. Here, Treg regulate the accu-
mulation of conventional CD8+ T cells as well as the
production of pro-inflammatory molecules in the
uterus and draining lymph nodes, thereby support-
ing embryo nidation by dampening inflammatory
processes occurring during the time of implanta-
tion.20
Fetal Treg – Immune regulation from the other site
of the placenta
Investigations on Treg contribution to fetal–maternal
tolerance were initially limited to the maternal side.
However, fetal immune cells and, in particular, fetal
Treg may be involved in fetal–maternal tolerance
mechanisms. More recent studies contributed to the
knowledge of the function of fetal Treg. According
to a study by Cupedo et al.,124 fetal Treg are gener-
ated in the thymus where they already gain the
potential to suppress the proliferation of CD25� cells.
After leaving the thymus, they enter fetal secondary
lymphoid organs and umbilical cord blood, where
they acquire a primed/memory phenotype and are
present in a high abundance.124–126 As the high
number of peripheral fetal Treg is not reflected in
the thymus, it is suggested that a significant propor-
tion of the peripheral Treg pool is expanded from
thymic Treg or is generated from conventional T
cells after antigen encounter.127 Encounter of non-
inherited maternal antigens (NIMAs) by fetal Treg
may occur in fetal lymph nodes and umbilical cord
blood where the presence of maternal cells has been
proven.128 Here, fetal immune responses against
maternal APCs bearing NIMAs can be dampened.
Thus, it can be assumed that both maternal and fetal
Treg are crucially involved in immune regulatory
processes that are indispensable for mother and child
to accept each other.
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Role of Treg in autoimmune diseases during
pregnancy
It has been reported that pregnancy is associated
with alterations in the disease activity of some auto-
immune diseases depending on the predominant
immunological course of the disease. Whereas Th1-
dominated autoimmune diseases such as multiple
sclerosis (MS) improve, Th2-dominated autoim-
mune diseases such as systemic lupus erythema-
todes (SLE) aggravate.129 As Treg are best known
for their function in preventing autoimmune dis-
eases, they have to be involved in the reduction in
disease activity observed for some autoimmune dis-
eases during pregnancy. Reduced Treg numbers and
impaired functionality as demonstrated in humans
and mice suffering from SLE130–136 may influence
pregnancy outcome. The adoptive transfer of Treg
in lupus-prone mice could reduce disease progres-
sion and improve survival137 suggesting clinical pos-
sibilities for therapeutic interventions in the future.
Consistent with the situation in lupus patients,
asthmatic patients are unable to augment their Treg
number during pregnancy. These patients showed
an abnormal asthma-dependent Th17 elevation
together with blunted Treg increase that may play a
role in the compromised immune tolerance charac-
terizing asthmatic pregnancy.138 In contrast, it is
known that pregnancy has a beneficial effect on
disease progression of rheumatoid arthritis. In a
murine model of arthritis, Munoz-Suano et al.139
demonstrated that Treg were responsible for the
pregnancy-induced amelioration of arthritis. In
agreement, in humans, improvement in disease
activity in the third trimester corresponded to
increased Treg numbers that induced a pronounced
anti-inflammatory cytokine milieu.140 MS patients
experience a significant reduction in their disease
activity especially during the third trimester of preg-
nancy. However, contribution of Treg to disease
amelioration is questionable as Treg number seems
not to differ between healthy pregnant women and
pregnant patients with MS.141 Here, pregnancy hor-
mones were suggested to be responsible for disease
improvement, and some of them are known to
influence Treg. In this regard, Wang et al.142 nicely
proved that administration of E2 at pregnancy levels
in a murine model of MS, namely experimental
autoimmune encephalitis, enhanced Treg frequency
and suppressed the disease.
Role of Treg in infections during pregnancy
Systemic and local infections occurring during preg-
nancy are a big challenge for the maternal immune
system, as it has to attack pathogens while at the
same time tolerate foreign fetal antigens. When
the infection is overwhelming, as a consequence,
the fetus is often rejected. LPS administration, used
to mimic bacterial infection, to normal pregnant
mice at mid-gestation has been shown to result in
preterm delivery. In this murine model of LPS-
induced preterm delivery, CD4+ T cells are proposed
to play a protective but not indispensable role.143 In
infections with Tritrichomonas foetus, Foxp3, Th17
and Th1 cells are augmented and embryonic death is
suggested to result from an exacerbated effector
response of type 1 and 17. Additionally, increased
Treg number may contribute to worsen pregnancy
outcome by promoting persistence of infection.144
Pregnancy-associated Treg increase also causes
enhanced susceptibility to prenatal pathogens
including Listeria and Salmonella species. However,
expansion of Treg is essential to protect the fetus
from rejection. Thus, maternal Treg augmentation
required for maintaining pregnancy creates naturally
occurring holes in host defense that confer prenatal
bacterial susceptibility.145 Parasite infections of preg-
nant women with Toxoplasma gondii or Plasmodium
falciparum result in an imbalance of the Treg/Th17
ratio, with reduced Treg numbers and increased
Th17 frequencies.146–148 This suggests that embryo
loss caused by these parasites may be associated with
a reduced Treg/Th17 ratio.149 Finally, viral infection
with the human immunodeficiency virus (HIV) is
characterized by CD4+ T-cell depletion, chronic
immune activation and altered lymphocyte subsets
that may have importance for the induction of fetal–maternal tolerance and in part explain the increased
risk of abortion in HIV-infected women.150
Role of Treg in assisted reproductive techniques
and their therapeutic potential
Based on a growing body of knowledge, there is a
particular interest to employ Treg as a therapeutic
target to support women in getting pregnant and
treat patients with pregnancy complications. There is
evidence that the success of assisted reproductive
techniques (ART) such as artificial inseminations
and in vitro fertilization (IVF)/intracytoplasmic sperm
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injection (ICSI) can be predicted by Treg frequencies.
In this regard, it has been shown that enhanced
pregnancy rates and live birth rates are associated
with increased Treg before and after ART.151,152
More precisely, Schlossberger et al. defined Treg
subpopulations after IVF/ICSI treatment. They found
that non-successfully IVF/ICSI-treated women have
a decreased percentage of naive CD45RA+ Treg and
an increased percentage of HLA-DR� memory Treg
within the total Treg pool. However, the percentage
of CD4+CD127lowCD25+Foxp3+ Treg within the
CD4+ T-cell pool did not differ between IVF/ICSI-
treated women who did or did not become
pregnant.153 During pregnancy, prevention of spon-
taneous abortion by adoptive Treg transfer has been
proven to work in the murine system4,91 and may
be applicable for RSA patients known to have
reduced Treg frequencies. A promising approach is
to immunize URSA patients with paternal leukocytes
shown to improve pregnancy outcome.154 Interest-
ingly, the proportion of CD4+CD25bright T cells in
peripheral blood from URSA patients increased sig-
nificantly after paternal or third-party lymphocyte
immunization therapy, whereas the percentage of
CD4+CD25dim T cells decreased significantly. Impor-
tantly, the percentage of CD4+CD25bright T cells was
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esen
tatio
n
Paraaortic lymph nodes Feto-maternal interface
Treg
APC
Paternal antigens(seminal vesicle)
hCG, chemokines
TregTolerogenic DCs
Peripheral blood
Maternal Treg
Teff Fetal Treg
Fetal Treg
hCGHO-1
MaternalTreg DCs
Tolerogenic DCs
TGF-β
Thymus
Non-pregnant uterus
Fibrosisinflammation
CCR7/CCL19
Fig. 1 This hypothetical cartoon depicts the issues discussed within this reviews about the pathways involved in the origin and expansion of
Treg. Thymus-originated Treg migrate to the uterus where they contribute to the generation of a friendly environment for the embryo to implant,
and this occurs independently of pregnancy and is mediated by CCL19/CCR7. Paternal antigens are presented to the maternal immune system in
the vaginal lumen after the encounter of maternal/paternal immune cells with antigens present in the seminal fluid. The seminal fluid contains also
substances that promote the conversion of dendritic cells (DCs) in tolerogenic ones. This promotes the conversion and expansion of regulatory T
cells (Treg). The continuous release of paternal antigens to the circulation allows that Treg continue emerging and expanding throughout
pregnancy in, for example, the para-aortic lymph nodes. In peripheral blood, Treg are likely involved in the suppression of maternal effector T
cells that could be harmful to fetal antigens present here as well as in several maternal tissues. Treg migrate to the fetal–maternal interface via
human chorionic gonadotropin (hCG). At the feto–maternal interface, a broad spectrum of molecules produced or secreted by the trophoblast
itself like hCG and HO-1 modulate the phenotype of function of immune cells.
American Journal of Reproductive Immunology 72 (2014) 158–170
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significantly higher in successfully pregnant women
than in those with pregnancy loss after lymphocyte
therapy.155 A possible explanation for the success of
the immunotherapy is provided by Sugi et al. who
reported changes in the mixed lymphocyte reaction
(MLR), T-cell subsets and generation of anti-idiotyp-
ic antibodies after immunotherapy with paternal
leukocytes. The percentage of cytotoxic T cells was
significantly decreased, and the percentage of sup-
pressor T cells was significantly increased, suggesting
that a cell-mediated immune response was induced
by the immunotherapy.156
Conclusions
Treg are potent immunoregulators, and the exten-
sive revision of the literature highlights their func-
tion at every pregnancy stage as well as their
dysregulation during pregnancy pathologies. They
have a great potential as diagnostic and therapeutic
toll to monitor risk pregnancies. The concepts dis-
cussed in this review are summarized in Fig. 1.
References
1 Gershon RK, Kondo K: Cell interactions in the induction of
tolerance: the role of thymic lymphocytes. Immunology 1970;
18:723–737.
2 Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M:
Immunologic self-tolerance maintained by activated T cells
expressing IL-2 receptor alpha-chains (CD25). Breakdown of a
single mechanism of self-tolerance causes various autoimmune
diseases. J Immunol 1995; 155:1151–1164.
3 Aluvihare VR, Kallikourdis M, Betz AG: Regulatory T cells mediate
maternal tolerance to the fetus. Nat Immunol 2004; 5:266–271.
4 Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Bertoja AZ,
Ritter T, Kotsch K, Leber J, Volk H: Abnormal T-cell reactivity
against paternal antigens in spontaneous abortion: adoptive
transfer of pregnancy-induced CD4+CD25+ T regulatory cells
prevents fetal rejection in a murine abortion model. Am J Pathol
2005; 166:811–822.
5 Heikkinen J, M€ott€onen M, Alanen A, Lassila O: Phenotypic
characterization of regulatory T cells in the human decidua. Clin
Exp Immunol 2004; 136:373–378.
6 Saito S, Sasaki Y, Sakai M: CD4(+)CD25high regulatory T cells in
human pregnancy. J Reprod Immunol 2005; 65:111–120.
7 Weiner HL: Induction and mechanism of action of transforming
growth factor-beta-secreting Th3 regulatory cells. Immunol Rev
2001; 182:207–214.
8 Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK:
Type 1 T regulatory cells. Immunol Rev 2001; 182:68–79.
9 Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb
PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger
C, Soper DM, Ziegler SF, Bluestone JA: CD127 expression
inversely correlates with FoxP3 and suppressive function of
human CD4+ T reg cells. J Exp Med 2006; 203:1701–1711.
10 McHugh RS, Shevach EM: Cutting edge: depletion of CD4+CD25+
regulatory T cells is necessary, but not sufficient, for induction of
organ-specific autoimmune disease. J Immunol 2002; 168:5979–
5983.
11 Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi
N, Mak TW, Sakaguchi S: Immunologic self-tolerance maintained
by CD25(+)CD4(+) regulatory T cells constitutively expressing
cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;
192:303–310.
12 Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG,
Rudensky AY: Regulatory T cell lineage specification by the
forkhead transcription factor foxp3. Immunity 2005; 22:329–341.
13 Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky
AY: Extrathymic generation of regulatory T cells in placental
mammals mitigates maternal-fetal conflict. Cell 2012; 150:29–38.
14 Teles A, Thuere C, Wafula PO, El-Mousleh T, Zenclussen ML,
Zenclussen AC: Origin of Foxp3(+) cells during pregnancy. Am J
Clin Exp Immunol 2013; 2:222–233.
15 Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N, McGrady G,
Wahl SM: Conversion of peripheral CD4+CD25- naive T cells to
CD4+CD25+ regulatory T cells by TGF-beta induction of
transcription factor Foxp3. J Exp Med 2003; 198:1875–1886.
16 Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig
MC, von Boehmer H: Inducing and expanding regulatory
T cell populations by foreign antigen. Nat Immunol 2005;
6:1219–1227.
17 Sollwedel A, Bertoja AZ, Zenclussen ML, Gerlof K, Lisewski U,
Wafula P, Sawitzki B, Woiciechowsky C, Volk H, Zenclussen AC:
Protection from abortion by heme oxygenase-1 up-regulation is
associated with increased levels of Bag-1 and neuropilin-1 at the
fetal-maternal interface. J Immunol 2005; 175:4875–4885.
18 Arruvito L, Sanz M, Banham AH, Fainboim L: Expansion of
CD4+CD25+ and FOXP3+ regulatory T cells during the follicular
phase of the menstrual cycle: implications for human
reproduction. J Immunol 2007; 178:2572–2578.
19 Kallikourdis M, Betz AG: Periodic accumulation of regulatory T
cells in the uterus: preparation for the implantation of a semi-
allogeneic fetus? PLoS One 2007; 2:e382.
20 Teles A, Schumacher A, K€uhnle M, Linzke N, Thuere C, Reichardt
P, Tadokoro CE, H€ammerling GJ, Zenclussen AC: Control of
uterine microenvironment by Foxp3+ cells facilitates embryo
implantation. Front Immunol 2013; 4:158.
21 Weinberg A, Enomoto L, Marcus R, Canniff J: Effect of menstrual
cycle variation in female sex hormones on cellular immunity and
regulation. J Reprod Immunol 2011; 89:70–77.
22 Xiong Y, Yuan Z, He L: Effects of estrogen on CD4(+) CD25(+)
regulatory T cell in peripheral blood during pregnancy. Asian Pac J
Trop Med 2013; 6:748–752.
23 Tilburgs T, Roelen DL, van der Mast BJ, van Schip JJ, Kleijburg C,
de Groot-Swings GM, Kanhai HHH, Claas FHJ, Scherjon SA:
Differential distribution of CD4(+)CD25(bright) and CD8(+)CD28
(�) T-cells in decidua and maternal blood during human
pregnancy. Placenta 2006; 27:S47–S53.
24 Mj€osberg J, Svensson J, Johansson E, Hellstr€om L, Casas R,
Jenmalm MC, Boij R, Matthiesen L, J€onsson J, Berg G, Ernerudh
J: Systemic reduction of functionally suppressive
CD4dimCD25highFoxp3+ Tregs in human second trimester
pregnancy is induced by progesterone and 17beta-estradiol.
J Immunol 2009; 183:759–769.
25 Seol H, Oh M, Lim J, Jung N, Yoon S, Kim H: The role of
CD4+CD25bright regulatory T cells in the maintenance of
American Journal of Reproductive Immunology 72 (2014) 158–170
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 165
REGULATORY T CELLS DURING PREGNANCY
![Page 9: Regulatory T Cells: Regulators of Life](https://reader031.vdocument.in/reader031/viewer/2022020203/5750a0a41a28abcf0c8d9e09/html5/thumbnails/9.jpg)
pregnancy, premature rupture of membranes, and labor. Yonsei
Med J 2008; 49:366.
26 Xiong H, Zhou C, Qi G: Proportional changes of
CD4+CD25+Foxp3+ regulatory T cells in maternal peripheral blood
during pregnancy and labor at term and preterm. Clin Invest Med
2010; 33:E422.
27 Galazka K, Wicherek L, Pitynski K, Kijowski J, Zajac K, Bednarek
W, Dutsch-Wicherek M, Rytlewski K, Kalinka J, Basta A, Majka
M: Original article: changes in the subpopulation of CD25+ CD4+
and FOXP3+ regulatory T cells in decidua with respect to the
progression of labor at term and the lack of analogical changes in
the subpopulation of suppressive B7-H4+ macrophages – a
preliminar. Am J Reprod Immunol 2009; 61:136–146.
28 Kisielewicz A, Schaier M, Schmitt E, Hug F, Haensch GM, Meuer
S, Zeier M, Sohn C, Steinborn A: A distinct subset of HLA-DR+-
regulatory T cells is involved in the induction of preterm labor
during pregnancy and in the induction of organ rejection after
transplantation. Clin Immunol 2010; 137:209–220.
29 Thuere C, Zenclussen ML, Schumacher A, Langwisch S, Schulte-
Wrede U, Teles A, Paeschke S, Volk H, Zenclussen AC: Kinetics of
regulatory T cells during murine pregnancy. Am J Reprod Immunol
2007; 58:514–523.
30 Steinborn A, Schmitt E, Kisielewicz A, Rechenberg S, Seissler N,
Mahnke K, Schaier M, Zeier M, Sohn C: Pregnancy-associated
diseases are characterized by the composition of the systemic
regulatory T cell (Treg) pool with distinct subsets of Tregs. Clin Exp
Immunol 2012; 167:84–98.
31 Shao L, Jacobs AR, Johnson VV, Mayer L: Activation of CD8+
regulatory T cells by human placental trophoblasts. J Immunol
2005; 174:7539–7547.
32 Tilburgs T, Schonkeren D, Eikmans M, Nagtzaam NM, Datema G,
Swings GM, Prins F, van Lith JM, van der Mast BJ, Roelen DL,
Scherjon SA, Claas FH: Human decidual tissue contains
differentiated CD8+ effector-memory T cells with unique
properties. J Immunol 2010; 185:4470–4477.
33 Mincheva-Nilsson L, Hammarstr€om S, Hammarstr€om ML: Human
decidual leukocytes from early pregnancy contain high numbers of
gamma delta+ cells and show selective down-regulation of
alloreactivity. J Immunol 1992; 149:2203–2211.
34 Yan Z, Lambert NC, Guthrie KA, Porter AJ, Loubiere LS,
Madeleine MM, Stevens AM, Hermes HM, Nelson JL: Male
microchimerism in women without sons: quantitative assessment
and correlation with pregnancy history. Am J Med 2005;
118:899–906.
35 Tan X, Liao H, Sun L, Okabe M, Xiao Z, Dawe GS: Fetal
microchimerism in the maternal mouse brain: a novel population
of fetal progenitor or stem cells able to cross the blood-brain
barrier? Stem Cells 2005; 23:1443–1452.
36 Khosrotehrani K, Johnson KL, Gu�egan S, Stroh H, Bianchi DW:
Natural history of fetal cell microchimerism during and following
murine pregnancy. J Reprod Immunol 2005; 66:1–12.
37 Dutta P, Molitor-Dart M, Bobadilla JL, Roenneburg DA, Yan Z,
Torrealba JR, Burlingham WJ: Microchimerism is strongly
correlated with tolerance to noninherited maternal antigens in
mice. Blood 2009; 114:3578–3587.
38 Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg-
V D, Voort-Maarschalk M, Roelen DL, van Rood JJ, Claas FHJ:
Fetal-maternal HLA-C mismatch is associated with decidual T cell
activation and induction of functional T regulatory cells. J Reprod
Immunol 2009; 82:148–157.
39 Darrasse-J�eze G, Darasse-J�eze G, Klatzmann D, Charlotte F,
Salomon BL, Cohen JL: CD4+CD25+ regulatory/suppressor T cells
prevent allogeneic fetus rejection in mice. Immunol Lett 2006;
102:106–109.
40 Mj€osberg J, Berg G, Ernerudh J, Ekerfelt C: CD4+ CD25+
regulatory T cells in human pregnancy: development of a Treg-
MLC-ELISPOT suppression assay and indications of paternal
specific Tregs. Immunology 2007; 120:456–466.
41 Schumacher A, Wafula PO, Bertoja AZ, Sollwedel A, Thuere C,
Wollenberg I, Yagita H, Volk H, Zenclussen AC: Mechanisms of
action of regulatory T cells specific for paternal antigens during
pregnancy. Obstet Gynecol 2007; 110:1137–1145.
42 Kallikourdis M, Andersen KG, Welch KA, Betz AG: Alloantigen-
enhanced accumulation of CCR5+ ‘effector’ regulatory T cells in
the gravid uterus. Proc Natl Acad Sci USA 2007; 104:594–599.
43 Kahn DA, Baltimore D: Pregnancy induces a fetal antigen-specific
maternal T regulatory cell response that contributes to tolerance.
Proc Natl Acad Sci USA 2010; 107:9299–9304.
44 Moldenhauer LM, Diener KR, Thring DM, Brown MP, Hayball JD,
Robertson SA: Cross-presentation of male seminal fluid antigens
elicits T cell activation to initiate the female immune response to
pregnancy. J Immunol 2009; 182:8080–8093.
45 Zenclussen ML, Thuere C, Ahmad N, Wafula PO, Fest S, Teles A,
Leber A, Casalis PA, Bechmann I, Priller J, Volk H, Zenclussen AC:
The persistence of paternal antigens in the maternal body is
involved in regulatory T-cell expansion and fetal-maternal
tolerance in murine pregnancy. Am J Reprod Immunol 2010;
63:200–208.
46 Robertson SA, Guerin LR, Bromfield JJ, Branson KM, Ahlstr€om
AC, Care AS: Seminal fluid drives expansion of the CD4+CD25+ T
regulatory cell pool and induces tolerance to paternal alloantigens
in mice. Biol Reprod 2009; 80:1036–1045.
47 Guerin LR, Moldenhauer LM, Prins JR, Bromfield JJ, Hayball JD,
Robertson SA: Seminal fluid regulates accumulation of FOXP3+
regulatory T cells in the preimplantation mouse uterus through
expanding the FOXP3+ cell pool and CCL19-mediated recruitment.
Biol Reprod 2011; 85:397–408.
48 Balandya E, Wieland-Alter W, Sanders K, Lahey T: Human
seminal plasma fosters CD4(+) regulatory T-cell phenotype and
transforming growth factor-b1 expression. Am J Reprod Immunol
2012; 68:322–330.
49 Liu C, Wang X, Sun X: Assessment of sperm antigen specific T
regulatory cells in women with recurrent miscarriage. Early Human
Dev 2013; 89:95–100.
50 Clark DA, Fernandes J, Fernandez J, Banwatt D: Prevention of
spontaneous abortion in the CBA x DBA/2 mouse model by
intravaginal TGF-beta and local recruitment of CD4+8+ FOXP3+
cells. Am J Reprod Immunol 2008; 59:525–534.
51 Schober L, Radnai D, Schmitt E, Mahnke K, Sohn C, Steinborn A:
Term and preterm labor: decreased suppressive activity and
changes in composition of the regulatory T-cell pool. Immunol Cell
Biol 2012; 90:935–944.
52 Rowe JH, Ertelt JM, Xin L, Way SS: Pregnancy imprints regulatory
memory that sustains anergy to fetal antigen. Nature 2012;
490:102–106.
53 Tilburgs T, Roelen DL, van der Mast BJ, de Groot-Swings GM,
Kleijburg C, Scherjon SA, Claas FH: Evidence for a selective
migration of fetus-specific CD4+CD25bright regulatory T cells from
the peripheral blood to the decidua in human pregnancy.
J Immunol 2008; 180:5737–5745.
American Journal of Reproductive Immunology 72 (2014) 158–170
166 ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SCHUMACHER AND ZENCLUSSEN
![Page 10: Regulatory T Cells: Regulators of Life](https://reader031.vdocument.in/reader031/viewer/2022020203/5750a0a41a28abcf0c8d9e09/html5/thumbnails/10.jpg)
54 Schumacher A, Brachwitz N, Sohr S, Engeland K, Langwisch S,
Dolaptchieva M, Alexander T, Taran A, Malfertheiner SF, Costa S,
Zimmermann G, Nitschke C, Volk H, Alexander H, Gunzer M,
Zenclussen AC: Human chorionic gonadotropin attracts regulatory
T cells into the fetal-maternal interface during early human
pregnancy. J Immunol 2009; 182:5488–5497.
55 Ramhorst R, Fraccaroli L, Aldo P, Alvero AB, Cardenas I, Leir�os
CP, Mor G: Modulation and recruitment of inducible regulatory T
cells by first trimester trophoblast cells. Am J Reprod Immunol 2012;
67:17–27.
56 Caballero-Campo P, Dom�ınguez F, Coloma J, Meseguer M,
Remoh�ı J, Pellicer A, Sim�on C: Hormonal and embryonic
regulation of chemokines IL-8, MCP-1 and RANTES in the human
endometrium during the window of implantation. Mol Hum Reprod
2002; 8:375–384.
57 Jones RL, Hannan NJ, Kaitu’u TJ, Zhang J, Salamonsen LA:
Identification of chemokines important for leukocyte recruitment
to the human endometrium at the times of embryo implantation
and menstruation. J Clin Endocrinol Metab 2004; 89:6155–6167.
58 Red-Horse K, Drake PM, Gunn MD, Fisher SJ: Chemokine ligand
and receptor expression in the pregnant uterus: reciprocal patterns
in complementary cell subsets suggest functional roles. Am J Pathol
2001; 159:2199–2213.
59 Lin Y, Xu L, Jin H, Zhong Y, Di J, Lin Q: CXCL12 enhances
exogenous CD4+CD25+ T cell migration and prevents embryo loss
in non-obese diabetic mice. Fertil Steril 2009; 91:2687–2696.
60 Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E, Hancock WW:
Recruitment of Foxp3+ T regulatory cells mediating allograft
tolerance depends on the CCR4 chemokine receptor. J Exp Med
2005; 201:1037–1044.
61 Schumacher A, Heinze K, Witte J, Poloski E, Linzke N, Woidacki
K, Zenclussen AC: Human chorionic gonadotropin as a central
regulator of pregnancy immune tolerance. J Immunol 2013;
190:2650–2658.
62 Gridelet V, Tsampalas M, Berndt S, Hagelstein M, Charlet-Renard
C, Conrath V, Ectors F, Hug�e F, Munaut C, Foidart J, Geenen V,
Perrier d’Hauterive S: Evidence for cross-talk between the LH
receptor and LH during implantation in mice. Reprod Fertil Dev
2013; 25:511.
63 Andersen KG, Nissen JK, Betz AG: Comparative genomics reveals
key gain-of-function events in Foxp3 during regulatory T cell
evolution. Front Immunol 2012; 3:113.
64 Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT:
Normal human pregnancy is associated with an elevation in the
immune suppressive CD25+ CD4+ regulatory T-cell subset.
Immunology 2004; 112:38–43.
65 Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S:
Decidual and peripheral blood CD4+CD25+ regulatory T cells in
early pregnancy subjects and spontaneous abortion cases. Mol Hum
Reprod 2004; 10:347–353.
66 Yang H, Qiu L, Chen G, Ye Z, L€u C, Lin Q: Proportional change of
CD4+CD25+ regulatory T cells in decidua and peripheral blood in
unexplained recurrent spontaneous abortion patients. Fertil Steril
2008; 89:656–661.
67 Jin L, Chen Q, Zhang T, Guo P, Li D: The CD4+CD25 bright
regulatory T cells and CTLA-4 expression in peripheral and
decidual lymphocytes are down-regulated in human miscarriage.
Clin Immunol 2009; 133:402–410.
68 Arruvito L, Sotelo AI, Billordo A, Fainboim L: A physiological role
for inducible FOXP3+ TREG cells. Clin Immunol 2010;
136:432–441.
69 Mei S, Tan J, Chen H, Chen Y, Zhang J: Changes of
CD4+CD25high regulatory T cells and FOXP3 expression in
unexplained recurrent spontaneous abortion patients. Fertil Steril
2010; 94:2244–2247.
70 Inada K, Shima T, Nakashima A, Aoki K, Ito M, Saito S:
Characterization of regulatory T cells in decidua of miscarriage
cases with abnormal or normal fetal chromosomal content.
J Reprod Immunol 2013; 97:104–111.
71 Jin L, Li D, Zhang J, Wang M, Zhu X, Zhu Y, Meng Y, Yuan M:
Adoptive transfer of paternal antigen-hyporesponsive T cells
induces maternal tolerance to the allogeneic fetus in abortion-
prone matings. J Immunol 2004; 173:3612–3619.
72 Winger EE, Reed JL: Low circulating CD4(+) CD25(+) Foxp3(+) T
regulatory cell levels predict miscarriage risk in newly pregnant
women with a history of failure. Am J Reprod Immunol 2011;
66:320–328.
73 Arruvito L, Billordo A, Capucchio M, Prada M, Fainboim L: IL-6
trans-signaling and the frequency of CD4+FOXP3+ cells in women
with reproductive failure. J Reprod Immunol 2009; 82:158–165.
74 Wang WJ, Hao CF, Yi-Lin, Yin GJ, Bao SH, Qiu LH, Lin QD:
Increased prevalence of T helper 17 (Th17) cells in peripheral
blood and decidua in unexplained recurrent spontaneous abortion
patients. J Reprod Immunol 2010; 84:164–170.
75 Basta P, Majka M, Jozwicki W, Lukaszewska E, Knafel A, Grabiec
M, Stasienko E, Wicherek L: The frequency of CD25+CD4+ and
FOXP3+ regulatory T cells in ectopic endometrium and ectopic
decidua. Reprod Biol Endocrinol 2010; 8:116.
76 Sundara Y: Decidual infiltration of FoxP3+ regulatory T€ı¿½cells,
CD3+ T€ı¿½cells, CD56+ decidual natural killer cells and Ki-67
trophoblast cells in hydatidiform mole compared to normal and
ectopic pregnancies. Mol Med Rep 2012; 5:275–281.
77 Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima
T, Shiozaki A, Rolinski J, Saito S: Proportion of peripheral blood
and decidual CD4(+) CD25(bright) regulatory T cells in pre-
eclampsia. Clin Exp Immunol 2007; 149:139–145.
78 Toldi G, �Svec P, V�as�arhelyi B, M�esz�aros G, Rig�o J, Tulassay T,
Treszl A: Decreased number of FoxP3+ regulatory T cells in
preeclampsia. Acta Obstet Gynecol Scand 2008; 87:1229–1233.
79 Prins JR, Boelens HM, Heimweg J, van der Heide S, Dubois AE,
van Oosterhout AJ, Erwich JJHM: Preeclampsia is associated with
lower percentages of regulatory T cells in maternal blood.
Hypertens Pregnancy 2009; 28:300–311.
80 Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas
de St Groth B, Nanan R: Systemic increase in the ratio between
Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy
but not in preeclampsia. J Immunol 2009; 183:7023–7030.
81 Quinn KH, Lacoursiere DY, Cui L, Bui J, Parast MM: The unique
pathophysiology of early-onset severe preeclampsia: role of
decidual T regulatory cells. J Reprod Immunol 2011; 91:76–82.
82 Toldi G, Saito S, Shima T, Halmos A, Veresh Z, V�as�arhelyi B, Rig�o
J, Molvarec A: The frequency of peripheral blood CD4+ CD25high
FoxP3+ and CD4+ CD25- FoxP3+ regulatory T cells in normal
pregnancy and pre-eclampsia. Am J Reprod Immunol 2012;
68:175–180.
83 Darmochwal-Kolarz D, Kludka-Sternik M, Tabarkiewicz J, Kolarz
B, Rolinski J, Leszczynska-Gorzelak B, Oleszczuk J: The
predominance of Th17 lymphocytes and decreased number and
function of Treg cells in preeclampsia. J Reprod Immunol 2012;
93:75–81.
84 Zeng B, Kwak-Kim J, Liu Y, Liao A: Treg cells are negatively
correlated with increased memory B cells in pre-eclampsia while
American Journal of Reproductive Immunology 72 (2014) 158–170
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 167
REGULATORY T CELLS DURING PREGNANCY
![Page 11: Regulatory T Cells: Regulators of Life](https://reader031.vdocument.in/reader031/viewer/2022020203/5750a0a41a28abcf0c8d9e09/html5/thumbnails/11.jpg)
maintaining suppressive function on autologous B-cell
proliferation. Am J Reprod Immunol 2013; 70:454–463.
85 Paeschke S, Chen F, Horn N, Fotopoulou C, Zambon-Bertoja A,
Sollwedel A, Zenclussen ML, Casalis PA, Dudenhausen JW, Volk
H, Zenclussen AC: Pre-eclampsia is not associated with changes in
the levels of regulatory T cells in peripheral blood. Am J Reprod
Immunol 2005; 54:384–389.
86 Hu D, Chen Y, Zhang W, Wang H, Wang Z, Dong M: Alteration of
peripheral CD 4+ CD 25+ regulatory T lymphocytes in pregnancy
and pre-eclampsia. Acta Obstet Gynecol Scand 2008; 87:190–194.
87 Hsu P, Santner-Nanan B, Dahlstrom JE, Fadia M, Chandra A, Peek
M, Nanan R: Altered decidual DC-SIGN(+) antigen-presenting cells
and impaired regulatory T-cell induction in preeclampsia. Am J
Pathol 2012; 181:2149–2160.
88 Darmochwal-Kolarz D, Saito S, Tabarkiewicz J, Kolarz B, Rolinski
J, Leszczynska-Gorzelak B, Oleszczuk J: Apoptosis signaling is
altered in CD4+CD25+FoxP3+ T regulatory lymphocytes in pre-
eclampsia. Int J Mol Sci 2012; 13:6548–6560.
89 Shima T, Sasaki Y, Itoh M, Nakashima A, Ishii N, Sugamura K,
Saito S: Regulatory T cells are necessary for implantation and
maintenance of early pregnancy but not late pregnancy in
allogeneic mice. J Reprod Immunol 2010; 85:121–129.
90 Clark DA, McDermott MR, Szewczuk MR: Impairment of host-
versus-graft reaction in pregnant mice. II. Selective suppression of
cytotoxic T-cell generation correlates with soluble suppressor
activity and with successful allogeneic pregnancy. Cell Immunol
1980; 52:106–118.
91 Yin Y, Han X, Shi Q, Zhao Y, He Y: Adoptive transfer of CD4+CD25+
regulatory T cells for prevention and treatment of spontaneous
abortion. Eur J Obstet Gynecol Reprod Biol 2012; 161:177–181.
92 Jin L, Zhou Y, Wang M, Zhu X, Li D: Blockade of CD80 and CD86
at the time of implantation inhibits maternal rejection to the
allogeneic fetus in abortion-prone matings. J Reprod Immunol 2005;
65:133–146.
93 Zhu X, Zhou Y, Wang M, Jin L, Yuan M, Li D: Blockade of CD86
signaling facilitates a Th2 bias at the maternal-fetal interface and
expands peripheral CD4+CD25+ regulatory T cells to rescue
abortion-prone fetuses. Biol Reprod 2005; 72:338–345.
94 Du M, Dong L, Zhou W, Yan F, Li D: Cyclosporin a improves
pregnancy outcome by promoting functions of trophoblasts and
inducing maternal tolerance to the allogeneic fetus in abortion-
prone matings in the mouse. Biol Reprod 2007; 76:906–914.
95 Li W, Li B, Fan W, Geng L, Li X, Li L, Huang Z, Li S: CTLA4Ig
gene transfer alleviates abortion in mice by expanding
CD4+CD25+ regulatory T cells and inducing indoleamine 2,3-
dioxygenase. J Reprod Immunol 2009; 80:1–11.
96 Chen T, Darrasse-Jeze G, Bergot A, Courau T, Churlaud G,
Valdivia K, Strominger JL, Ruocco MG, Chaouat G, Klatzmann D:
Self-specific memory regulatory T cells protect embryos at
implantation in mice. J Immunol 2013; 191:2273–2281.
97 D’Addio F, Riella LV, Mfarrej BG, Chabtini L, La Adams T, Yeung
M, Yagita H, Azuma M, Sayegh MH, Guleria I: The link between
the PDL1 costimulatory pathway and Th17 in fetomaternal
tolerance. J Immunol 2011; 187:4530–4541.
98 Yamauchi S, Izumi S, Shiotsuka Y, Watanabe K, Ozawa A:
Demonstration of HCG on the surface of maternal lymphocytes
and discrimination of T and B cells by esterase cytochemistry.
Tokai J Exp Clin Med 1983; 8:333–337.
99 Shirshev SV, Orlova EG, Zamorina SA, Nekrasova IV: Influence of
reproductive hormones on the induction of CD4(+)CD25 (bright)
Foxp (3+) regulatory T cells. Dokl Biol Sci 2011; 440:343–346.
100 Prieto GA, Rosenstein Y: Oestradiol potentiates the suppressive
function of human CD4 CD25 regulatory T cells by promoting
their proliferation. Immunology 2006; 118:58–65.
101 Polanczyk MJ, Hopke C, Vandenbark AA, Offner H: Estrogen-
mediated immunomodulation involves reduced activation of
effector T cells, potentiation of Treg cells, and enhanced expression
of the PD-1 costimulatory pathway. J Neurosci Res 2006; 84:370–378.
102 Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, Zhao L, An X, Du X,
Chen X, Wang S, Xia G, Wang B: Induction of regulatory T cells
by physiological level estrogen. J Cell Physiol 2008; 214:456–464.
103 Lin X, Zhou Q, Wang L, Gao Y, Zhang W, Luo Z, Chen B, Chen Z,
Chang S: Pregnancy estrogen drives the changes of T-lymphocyte
subsets and cytokines and prolongs the survival of H-Y skin graft
in murine model. Chin Med J 2010; 123:2593–2599.
104 Valor L, Teijeiro R, Aristimu~no C, Faure F, Alonso B, de Andr�es C,
Tejera M, L�opez-Lazareno N, Fern�andez-Cruz E, S�anchez-Ram�on
S: Estradiol-dependent perforin expression by human regulatory
T-cells. Eur J Clin Invest 2011; 41:357–364.
105 Holdstock G, Chastenay BF, Krawitt EL: Effects of testosterone,
oestradiol and progesterone on immune regulation. Clin Exp
Immunol 1982; 47:449–456.
106 Mao G, Wang J, Kang Y, Tai P, Wen J, Zou Q, Li G, Ouyang H,
Xia G, Wang B: Progesterone increases systemic and local uterine
proportions of CD4+CD25+ Treg cells during midterm pregnancy
in mice. Endocrinology 2010; 151:5477–5488.
107 Lee JH, Ulrich B, Cho J, Park J, Kim CH: Progesterone promotes
differentiation of human cord blood fetal T cells into T regulatory
cells but suppresses their differentiation into Th17 cells. J Immunol
2011; 187:1778–1787.
108 Piccirillo CA, Shevach EM: Cutting edge: control of CD8+ T cell
activation by CD4+CD25+ immunoregulatory cells. J Immunol
2001; 167:1137–1140.
109 Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, von
Boehmer H, von Andrian UH: Regulatory T cells reversibly
suppress cytotoxic T cell function independent of effector
differentiation. Immunity 2006; 25:129–141.
110 Ghiringhelli F, M�enard C, Terme M, Flament C, Taieb J, Chaput
N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C,
Blay J, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-
Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L:
CD4+CD25+ regulatory T cells inhibit natural killer cell functions
in a transforming growth factor-beta-dependent manner. J Exp
Med 2005; 202:1075–1085.
111 Lim HW, Hillsamer P, Banham AH, Kim CH: Cutting edge: direct
suppression of B cells by CD4+ CD25+ regulatory T cells. J
Immunol 2005; 175:4180–4183.
112 Cederbom L, Hall H, Ivars F: CD4+CD25+ regulatory T cells down-
regulate co-stimulatory molecules on antigen-presenting cells. Eur
J Immunol 2000; 30:1538–1543.
113 Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri
SV: Cutting edge: human CD4+CD25+ T cells restrain the
maturation and antigen-presenting function of dendritic cells.
J Immunol 2004; 172:4676–4680.
114 Taams LS, van Amelsfort JMR, Tiemessen MM, Jacobs KMG, de
Jong EC, Akbar AN, Bijlsma JWJ, Lafeber FPJG: Modulation of
monocyte/macrophage function by human CD4+CD25+ regulatory
T cells. Hum Immunol 2005; 66:222–230.
115 Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR,
Morris PJ, Powrie F, Wood KJ: IL-10 is required for regulatory T
cells to mediate tolerance to alloantigens in vivo. J Immunol 2001;
166:3789–3796.
American Journal of Reproductive Immunology 72 (2014) 158–170
168 ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SCHUMACHER AND ZENCLUSSEN
![Page 12: Regulatory T Cells: Regulators of Life](https://reader031.vdocument.in/reader031/viewer/2022020203/5750a0a41a28abcf0c8d9e09/html5/thumbnails/12.jpg)
116 Wahl SM, Swisher J, McCartney-Francis N, Chen W: TGF-beta:
the perpetrator of immune suppression by regulatory T cells and
suicidal T cells. J Leukoc Biol 2004; 76:15–24.
117 Friedline RH, Brown DS, Nguyen H, Kornfeld H, Lee J, Zhang Y,
Appleby M, Der SD, Kang J, Chambers CA: CD4+ regulatory T
cells require CTLA-4 for the maintenance of systemic tolerance.
J Exp Med 2009; 206:421–434.
118 Lu L, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos
K, Scott ZA, Coyle AJ, Reed JL, van Snick J, Strom TB, Zheng XX,
Noelle RJ: Mast cells are essential intermediaries in regulatory
T-cell tolerance. Nature 2006; 442:997–1002.
119 Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie ANJ,
Maurer M, Rosenkranz AR, Wolf AM: IL-9 production by
regulatory T cells recruits mast cells that are essential for
regulatory T cell-induced immune suppression. J Immunol 2011;
186:83–91.
120 Verdijk RM, Kloosterman A, Pool J, van de Keur M, Naipal AMIH,
van Halteren AGS, Brand A, Mutis T, Goulmy E: Pregnancy
induces minor histocompatibility antigen-specific cytotoxic T cells:
implications for stem cell transplantation and immunotherapy.
Blood 2004; 103:1961–1964.
121 Schumacher A, Wafula PO, Teles A, El-Mousleh T, Linzke N,
Zenclussen ML, Langwisch S, Heinze K, Wollenberg I, Casalis PA,
Volk H, Fest S, Zenclussen AC, Kassiotis G: Blockage of heme
oxygenase-1 abrogates the protective effect of regulatory T cells on
murine pregnancy and promotes the maturation of dendritic cells.
PLoS One 2012; 7:e42301.
122 Miwa N, Hayakawa S, Miyazaki S, Myojo S, Sasaki Y, Sakai M,
Takikawa O, Saito S: IDO expression on decidual and peripheral
blood dendritic cells and monocytes/macrophages after treatment
with CTLA-4 or interferon-gamma increase in normal pregnancy
but decrease in spontaneous abortion. Mol Hum Reprod 2005;
11:865–870.
123 Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ,
Marshall B, Brown C, Mellor AL: Prevention of allogeneic
fetal rejection by tryptophan catabolism. Science 1998; 281:1191–
1193.
124 Cupedo T, Nagasawa M, Weijer K, Blom B, Spits H: Development
and activation of regulatory T cells in the human fetus. Eur J
Immunol 2005; 35:383–390.
125 Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E:
Characterization of human CD25+ CD4+ T cells in thymus, cord
and adult blood. Immunology 2002; 106:190–199.
126 Lee C, Lin S, Cheng P, Kuo M: The regulatory function of
umbilical cord blood CD4(+) CD25(+) T cells stimulated with anti-
CD3/anti-CD28 and exogenous interleukin (IL)-2 or IL-15. Pediatr
Allergy Immunol 2009; 20:624–632.
127 Micha€elsson J, Mold JE, McCune JM, Nixon DF: Regulation of T
cell responses in the developing human fetus. J Immunol 2006;
176:5741–5748.
128 Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP,
Busch MP, Lee T, Nixon DF, McCune JM: Maternal alloantigens
promote the development of tolerogenic fetal regulatory T cells in
utero. Science 2008; 322:1562–1565.
129 Ostensen M, Brucato A, Carp H, Chambers C, Dolhain RJEM,
Doria A, Forger F, Gordon C, Hahn S, Khamashta M, Lockshin
MD, Matucci-Cerinic M, Meroni P, Nelson JL, Parke A, Petri M,
Raio L, Ruiz-Irastorza G, Silva CA, Tincani A, Villiger PM,
Wunder D, Cutolo M: Pregnancy and reproduction in
autoimmune rheumatic diseases. Rheumatology 2011; 50:657–664.
130 Hsu W, Suen J, Chiang B: The role of CD4CD25 T cells in
autoantibody production in murine lupus. Clin Exp Immunol 2006;
145:513–519.
131 Bonelli M, Savitskaya A, von Dalwigk K, Steiner CW, Aletaha D,
Smolen JS, Scheinecker C: Quantitative and qualitative
deficiencies of regulatory T cells in patients with systemic lupus
erythematosus (SLE). Int Immunol 2008; 20:861–868.
132 Crispin JC, Mart�ınez A, Alcocer-Varela J: Quantification of
regulatory T cells in patients with systemic lupus erythematosus.
J Autoimmun 2003; 21:273–276.
133 Bar�ath S, Solt�esz P, Kiss E, Aleksza M, Zeher M, Szegedi G, Sipka
S: The severity of systemic lupus erythematosus negatively
correlates with the increasing number of CD4+CD25(high)FoxP3+
regulatory T cells during repeated plasmapheresis treatments of
patients. Autoimmunity 2007; 40:521–528.
134 Barath S, Aleksza M, Tarr T, Sipka S, Szegedi G, Kiss E:
Measurement of natural (CD4+CD25high) and inducible (CD4+IL-
10+) regulatory T cells in patients with systemic lupus
erythematosus. Lupus 2007; 16:489–496.
135 Lyssuk EY, Torgashina AV, Soloviev SK, Nassonov EL, Bykovskaia
SN: Reduced number and function of CD4+CD25highFoxP3+
regulatory T cells in patients with systemic lupus erythematosus.
Adv Exp Med Biol 2007; 601:113–119.
136 Valencia X, Yarboro C, Illei G, Lipsky PE: Deficient CD4+CD25high
T regulatory cell function in patients with active systemic lupus
erythematosus. J Immunol 2007; 178:2579–2588.
137 Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI:
Suppression of disease in New Zealand Black/New Zealand White
lupus-prone mice by adoptive transfer of ex vivo expanded
regulatory T cells. J Immunol 2006; 177:1451–1459.
138 Toldi G, Molvarec A, Stenczer B, Muller V, Eszes N, Bohacs A,
Bikov A, Rigo J, Vasarhelyi B, Losonczy G, Tamasi L: Peripheral
Th1/Th2/Th17/regulatory T-cell balance in asthmatic pregnancy.
Int Immunol 2011; 23:669–677.
139 Munoz-Suano A, Kallikourdis M, Sarris M, Betz AG: Regulatory T
cells protect from autoimmune arthritis during pregnancy. J
Autoimmun 2012; 38:J103–J108.
140 F€orger F, Marcoli N, Gadola S, M€oller B, Villiger PM, Østensen M:
Pregnancy induces numerical and functional changes of
CD4+CD25 high regulatory T cells in patients with rheumatoid
arthritis. Ann Rheum Dis 2008; 67:984–990.
141 S�anchez-Ram�on S, Navarro AJ, Aristimu~no C, Rodr�ıguez-Mahou
M, Bell�on JM, Fern�andez-Cruz E, de Andr�es C: Pregnancy-
induced expansion of regulatory T-lymphocytes may mediate
protection to multiple sclerosis activity. Immunol Lett 2005; 96:195–
201.
142 Wang C, Dehghani B, Li Y, Kaler LJ, Vandenbark AA, Offner H:
Oestrogen modulates experimental autoimmune encephalomyelitis
and interleukin-17 production via programmed death 1.
Immunology 2009; 126:329–335.
143 Bizargity P, Del Rio R, Phillippe M, Teuscher C, Bonney EA:
Resistance to lipopolysaccharide-induced preterm delivery
mediated by regulatory T cell function in mice. Biol Reprod 2009;
80:874–881.
144 Woudwyk MA, Monteavaro CE, Jensen F, Soto P, Barbeito CG,
Zenclussen AC: Study of the uterine local immune response in a
murine model of embryonic death due to Tritrichomonas foetus. Am
J Reprod Immunol 2012; 68:128–137.
145 Rowe JH, Ertelt JM, Aguilera MN, Farrar MA, Way SS: Foxp3+
regulatory T cell expansion required for sustaining pregnancy
American Journal of Reproductive Immunology 72 (2014) 158–170
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 169
REGULATORY T CELLS DURING PREGNANCY
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compromises host defense against prenatal bacterial pathogens.
Cell Host Microbe 2011; 10:54–64.
146 Ge YY, Zhang L, Zhang G, Wu JP, Tan MJ, Hu W, Liang YJ, Wang
Y: In pregnant mice, the infection of Toxoplasma gondii causes the
decrease of CD4+ CD25+ -regulatory T cells. Parasite Immunol
2008; 30:471–481.
147 Chen J, Ge Y, Zhang J, Qiu X, Qiu J, Wu J, Wang Y, Sinai A: The
dysfunction of CD4+CD25+ regulatory T cells contributes to the
abortion of mice caused by Toxoplasma gondii excreted-secreted
antigens in early pregnancy. PLoS One 2013; 8:e69012.
148 Ibitokou S, Oesterholt M, Brutus L, Borgella S, Agbowa€ı C,
Ezinm�egnon S, Lusingu J, Schmiegelow C, Massougbodji A,
Deloron P, Troye-Blomberg M, Varani S, Luty AJF, Fievet N,
Penha-Goncalves C: Peripheral blood cell signatures of
Plasmodium falciparum infection during pregnancy. PLoS One 2012;
7:e49621.
149 Zhang H, Hu X, Liu X, Zhang R, Fu Q, Xu X: The Treg/Th17
imbalance in Toxoplasma gondii-infected pregnant mice. Am J
Reprod Immunol 2012; 67:112–121.
150 Kolte L, Gaardbo JC, Karlsson I, Sorensen AL, Ryder LP,
Skogstrand K, Ladelund S, Nielsen SD: Dysregulation of
CD4+CD25+CD127 low FOXP3+ regulatory T cells in HIV-infected
pregnant women. Blood 2011; 117:1861–1868.
151 Zhou J, Wang Z, Zhao X, Wang J, Sun H, Hu Y: An increase of
Treg cells in the peripheral blood is associated with a better in
vitro fertilization treatment outcome. Am J Reprod Immunol 2012;
68:100–106.
152 Lu Y, Zhang F, Zhang Y, Zeng B, Hu L, Liao A: Quantitative
reduction of peripheral CD4+ CD25+ FOXP3+ regulatory T cells in
reproductive failure after artificial insemination by donor sperm.
Am J Reprod Immunol 2013; 69:188–193.
153 Schlossberger V, Schober L, Rehnitz J, Schaier M, Zeier M, Meuer
S, Schmitt E, Toth B, Strowitzki T, Steinborn A: The success of
assisted reproduction technologies in relation to composition of
the total regulatory T cell (Treg) pool and different Treg subsets.
Hum Reprod 2013; 28:3062–3073.
154 Behar E, Carp H, Livneh A, Gazit E: Differential suppression
activity induced by paternal leukocyte immunization in habitual
abortion. Gynecol Obstet Invest 1993; 36:202–207.
155 Yang H, Qiu L, Di W, Zhao A, Chen G, Hu K, Lin Q: Proportional
change of CD4+CD25+ regulatory T cells after lymphocyte therapy
in unexplained recurrent spontaneous abortion patients. Fertil
Steril 2009; 92:301–305.
156 Sugi T, Makino T, Maruyama T, Kim WK, Iizuka R: A possible
mechanism of immunotherapy for patients with recurrent
spontaneous abortions. Am J Reprod Immunol 1991; 25:185–189.
American Journal of Reproductive Immunology 72 (2014) 158–170
170 ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SCHUMACHER AND ZENCLUSSEN