Download Pregnancy Complications and Unlocking the Enigma of Fetal

Regulatory T Cells: New Keys for Further
Unlocking the Enigma of Fetal Tolerance and
Pregnancy Complications
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of August 11, 2017.
Tony T. Jiang, Vandana Chaturvedi, James M. Ertelt,
Jeremy M. Kinder, Dayna R. Clark, Amy M. Valent, Lijun
Xin and Sing Sing Way
J Immunol 2014; 192:4949-4956; ;
doi: 10.4049/jimmunol.1400498
http://www.jimmunol.org/content/192/11/4949
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References
Brief Reviews
The
Journal of
Immunology
Regulatory T Cells: New Keys for Further Unlocking the
Enigma of Fetal Tolerance and Pregnancy Complications
Tony T. Jiang,*,† Vandana Chaturvedi,* James M. Ertelt,* Jeremy M. Kinder,*
Dayna R. Clark,* Amy M. Valent,‡ Lijun Xin,* and Sing Sing Way*
R
eproductive success in eutherian placental mammals
allowing prolonged in utero fetal maturation and
protection presents a conundrum whereby the mother
must tolerate, as well as provide nourishment to, the immunologically foreign fetus. More than 60 years ago, Sir Peter
Medawar (1) posited theories to explain how fetal tolerance
may occur, including physical separation between maternal
and fetal tissues, fetal antigenic immaturity, and maternal
immune suppression. Since then, evidence supporting the
partial validity of these explanations has been shown, with
more comprehensive molecular and cellular characterization
of maternal reproductive and fetal tissues. For example, entrapment of APCs within the decidua, local exclusion of effector T cells through chemokine gene silencing, and reduced
*Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; †Medical Scientist Training Program, University of Cincinnati
College of Medicine, Cincinnati, OH 45229; and ‡Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, OH 45229
Received for publication February 20, 2014. Accepted for publication March 20, 2014.
This work was supported by the National Institute of Allergy and Infectious Diseases
(Grants R01AI100934, R01AI087830, and R21AI112186 to S.S.W.) and the National
Institute of General Medical Sciences (Grant T32GM063483 to T.T.J.). S.S.W. holds
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400498
complement deposition together create a formidable immunological barrier (2–4). Similarly, the diminished or skewed
MHC expression by trophoblastic cells illustrates the additional contribution of antigenic immaturity in sustaining fetal
tolerance (5, 6). However, considering the increasingly established transfer of cellular vesicles or intact cells between
mother and fetus, as well as systemic recognition of the fetus
by maternal immune cells (7–9), these processes that work
locally at the maternal–fetal interface are likely incomplete
and implicate the necessity for complementary systemic immunological shifts.
Earlier studies showed that healthy pregnancies were associated with reduced IFN-g and reciprocally increased Th2
polarization of maternal PBMCs, whereas complications, such
as preeclampsia and spontaneous abortion, were each linked
with more IFN-g production (10). Although these findings
initially were interpreted to imply a requirement for maternal
Th2 CD4+ T cell polarization in sustaining fetal tolerance,
normal pregnancy outcomes in mice, despite individual or
combined defects in Th2 cytokines (e.g., IL-4, IL-5, IL-9, and
IL-13), refined these interpretations to instead implicate a
necessity for maintaining anti-Th1 responses (11, 12). More
recently, as additional CD4+ T cell subsets and non-Th1–
differentiation programs have been identified, our conceptual
understanding of the protective immunological changes that
occur during pregnancy has shifted in parallel.
In particular, the identification of regulatory T cells (Tregs)
as a distinct CD4+ T cell lineage dedicated to silencing activation of other immune components has rekindled the consideration of active immune suppression in many physiological
and disease processes. Most peripheral Tregs acquire Foxp3
expression within the thymus based on specificity for self-Ag
and suppress self-reactive immune components that escape
central tolerance (13). However, the additional capacity for
peripheral conversion of naive CD4+ T cells with specificity
for a near infinite array of immunologically foreign Ags into
Tregs establishes an adaptable arsenal of suppressive cells capable of responding to fluctuating environmental cues. In this
regard, Tregs have already been shown to restrain activation of
immune cells with commensal specificity that protects against
an Investigator in the Pathogenesis of Infectious Disease award from the Burroughs
Wellcome Fund.
Address correspondence and reprint requests to Dr. Sing Sing Way, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue,
MLC 7017, Cincinnati, OH 45229. E-mail address: [email protected]
Abbreviations used in this article: E, embryonic day; Treg, regulatory T cell.
Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00
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The immunological alterations required for successful
pregnancy in eutherian placental mammals have remained a scientific enigma since the discovery of MHC
haplotype diversity and unique immune signatures
among individuals. Within the past 10 years, accumulating data suggest that immune-suppressive regulatory
T cells (Tregs) confer essential protective benefits in sustaining tolerance to the semiallogeneic fetus during
pregnancy, along with their more established roles in
maintaining tolerance to self and “extended self” commensal Ags that averts autoimmunity. Reciprocally,
many human pregnancy complications stemming from
inadequacies in fetal tolerance have been associated
with defects in maternal Tregs. Thus, further elucidating the immunological shifts during pregnancy not
only have direct translational implications for improving perinatal health, they have enormous potential for
unveiling new clues about how Tregs work in other
biological contexts. In this article, epidemiological data
in human pregnancy and complementary animal studies implicating a pivotal protective role for maternal
Tregs are summarized. The Journal of Immunology,
2014, 192: 4949–4956.
4950
autoimmunity and refines immunity to pathogens (14–16).
In this review, accumulating evidence implicating extended
protective roles for Tregs in accommodating the expanded
repertoire of immunologically foreign Ags expressed by the
developing fetus during pregnancy is summarized (Fig. 1).
Treg homeostasis in uncomplicated human pregnancies
FIGURE 1. The necessity for expanded tolerance to encompass fetal/paternal Ags during pregnancy. Immune tolerance among the universe of all
possible Ags is selectively maintained for self and “extended-self” commensal
Ags in healthy individuals (left panel). During pregnancy, these targets of
immune tolerance expand to protect other immunologically foreign fetal/
paternal Ags expressed by the developing fetus (right panel).
(34) found that FOXP3 expression among maternal peripheral T cells was primarily restricted to the CD4dim CD25high
subset, and these cells declined by ∼50% in the second trimester of pregnancy. Interestingly, using other permutations
of CD25 or FOXP3 coexpression among CD4+ T cells, other
investigators (36, 37) linked diminishing peripheral Tregs
with migration into the decidua. However, several caveats
related to the analysis of human Tregs need to be considered
when evaluating these results in aggregate. The first is the high
degree of natural variation among individuals illustrated by
the wide range of peripheral Treg frequencies, even among
nonpregnant controls. The second relates to discordant markers
used for identifying human Tregs. Although Foxp3 is expressed exclusively by Tregs in mice (39, 40), FOXP3 expression in humans occurs for both immune-suppressive
Tregs and activated effector T cells (41, 42). To address this
limitation, expression of CD25 and/or downregulation of IL7R (CD127), along with Foxp3, have been used (Table I).
However, although high-level CD25 expression has consistently identified cells with suppressive properties in vitro, their
ability to restrain effector T cell activation in vivo remains
incompletely defined, and diminished CD127 expression that
more uniformly identifies suppressive cells has not been
consistently used (43, 44). Nevertheless, despite the inherent
heterogeneity among human individuals combined with
unique permutations of FOXP3, CD25, and expression of
other CD4+ T cell–intrinsic molecules used to identify Tregs,
the physiological accumulation of maternal Tregs during
pregnancy has been widely replicated (Table I). Moreover,
given the increasingly recognized functional specialization of
Treg subsets with regard to specificity or molecules used to
mediate context-specific immune suppression (39, 40, 45),
individual studies in which bulk maternal Tregs do not expand significantly does not necessarily negate their importance in pregnancy. Instead, uncovering the most critical
protective features of maternal Tregs will likely require analysis of distinct Treg subsets based on specificity and local
accumulation at the maternal–fetal interface.
Maternal Tregs and human pregnancy complications
Analysis of maternal Tregs in human pregnancy complications
provides additional evidence supporting their protective necessity. Blunted expansion and/or functional decline has been
described in many seemingly unrelated complications, such as
spontaneous abortion, preeclampsia, and prematurity, which
potentially share underlying defects in fetal tolerance (Table II).
Among women with preeclampsia compared with gestational
aged-matched controls, an ∼33% reduction in peripheral Treg
expansion has been consistently described using various combinations of molecular markers (CD25high CD4+, CD127low
CD25high CD4+, FOXP3+ CD4+) (17, 23, 26, 27, 29–33, 36,
46–58). Furthermore, a representative case series of 43 women
with preeclampsia showed that impaired Treg expansion was
further exacerbated by increased levels of IL-17–producing
CD4+ T cells (31). These findings are consistent with the
common developmental origins but dichotomous differentiation programming for Tregs and Th17 CD4+ T cells that
may explain pathologically elevated levels of proinflammatory
cytokines, such as IL-6 and TNF-a, during preeclampsia (59–
61). Moreover, systemic inflammation that occurs during
preeclampsia is likely fueled by defects in fetal tolerance,
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The importance of Tregs likely begins during the menstrual
cycle to render female reproductive tissues receptive to foreign
paternal–fetal Ags. Cyclic reproductive hormones leading up
to pregnancy have potent quantitative and qualitative impacts
on Tregs (17–21). For example, the magnitude of peripheral
maternal Treg expansion is tightly correlated with serum estradiol levels that progressively rise just prior to ovulation
(17). In turn, progesterone that accumulates in the luteal
phase after ovulation acts synergistically with TGF-b and IL-2
to induce Foxp3 expression and augment Treg suppression
(18, 19, 21). Thus, female reproductive hormones work together with immune cells in a fine-tuned fashion for pregnancy preparation.
Maternal Treg expansion during pregnancy was first described in a series of observations comparing CD25 expression
among maternal CD4+ T cells. Mahmoud et al. (22, 23) reported a 1.6-fold increase in CD25+ “activated” CD4+ T cells
in the peripheral blood of women during the third trimester
compared with nonpregnant controls. With awareness that
CD25 expression more likely identifies immune-suppressive
cells, greater expansion of maternal CD25+ CD4+ Tregs that
peak in the first and second trimesters of pregnancy were
subsequently described (24, 25). Moreover, in parallel with
accumulation of immunologically foreign fetal tissue at the
maternal–fetal interface, CD25+ CD4+ Tregs with increased
CTLA-4 expression were found within the decidua (25, 26).
Since these initial reports, a wealth of human epidemiological
studies have replicated these key findings. Collectively, they
provide a consensus that maternal Tregs expand from a baseline of 1–10% of peripheral CD4+ T cells to 3–25% by
midgestation, with subsequent contraction to near background levels later in pregnancy (Table I) (22–38).
Importantly, however, there have also been some notable
inconsistencies in Treg shifts during pregnancy. Mjösberg et al.
BRIEF REVIEWS: Tregs AND MATERNAL–FETAL TOLERANCE
The Journal of Immunology
Table I.
4951
Maternal Treg shifts among peripheral blood CD4+ T cells during uncomplicated human pregnancies
Trimester
First
Second
Third
Treg Marker
+
Ref.
1.5 (p , 0.01)
2.6 (p , 0.01)
1.3 (p , 0.05)
2.7 (p , 0.01)
Increase (p , 0.05)
Increase (p , 0.001)
Increase (NS)
2.5 (not reported)
1.9 (p , 0.01)
1.0 (NS)
1.4 (p , 0.01)
Increase (p , 0.001)
Increase (p , 0.001)
1.6 (p = 0.009)
1.6 (p , 0.05)
2.0 (not reported)
1.4 (NS)
1.2 (p , 0.0001)
1.2 (p , 0.05)
1.5 (p , 0.001)
1.0 (NS)
1.7 (p , 0.001)
0.7 (NS)
Increase (p , 0.01)
(24)
(25)
(26)
(27)
(30)
(35)
(36)
(24)
(25)
(28)
(34)
(35)
(36)
(22)
(23)
(24)
(28)
(29)
(31)
(31)
(32)
(33)
(35)
(38)
a
Restricted only to Helios2 cells.
CD25high = CD25bright.
considering that delivery of the fetus and placenta remains the
most definitive and only effective therapy (62). Thus, active
suppression of immune components targeting foreign fetal
tissue work in tandem with reproductive hormones and fetal
cells that induce Foxp3 expression to silence activation of
pathogenic effector T cells in healthy pregnancies (17–21,
63).
Quantitative defects in maternal Tregs also have been described in cases of spontaneous abortion (Table II). Sasaki
et al. (26) reported an ∼33% decline in peripheral blood
CD25bright CD4+ T cells among women with spontaneous
abortion compared with uncomplicated pregnancy. This
decline was even more pronounced for decidual Tregs:
CD25bright CD4+ T cells declined from 22% in cases of
elective abortion compared with 7% in spontaneous abortion (26, 30). Similarly, women with recurrent spontaneous
abortion consistently had 40–90% reductions in circulating
and decidual Tregs (Table II). Interestingly, along with these
quantitative Treg reductions, diminished suppressive potency
for maternal Tregs also likely contributes to recurrent pregnancy loss, because production of the suppressive cytokines
IL-10 and TGF-b by CD127dim CD25+ CD4+ T cells recovered from women with recurrent abortions were reduced
to 2 and 1%, respectively, compared with 9 and 14% among
gestational aged–matched controls (54). Reductions in Tregsuppressive potency also were described in preterm labor,
which further illustrates the importance of maintaining
qualitative shifts in suppressive function, along with quantitative expansion of these cells, throughout pregnancy (64).
Collectively, these associations between maternal Treg expansion in uncomplicated human pregnancies and blunted
accumulation in pregnancy complications establish the groundwork implicating a protective role for these cells in sustaining
fetal tolerance.
Lessons from animal pregnancy
Human studies, although instrumental in describing molecular
and cellular changes associated with pregnancy, are inherently
limited by ethical considerations that preclude experimental
manipulation and analysis of reproductive tissue required for
establishing the cause and effect relationship between maternal
Tregs and pregnancy outcomes. Fortunately, animal studies
have bypassed many of these roadblocks and, together, more
definitively demonstrate the protective necessity of maternal
Tregs. In turn, redirecting the wealth of transgenic mouse tools
to investigate fetal tolerance provides additional mechanistic
insights about how Tregs mediate immune tolerance in other
contexts besides pregnancy.
First, maternal Tregs accumulate with similar magnitude
and tempo in mice compared with humans during pregnancy
(Table III) (35, 65–73). Using inbred mouse strains with
discordant MHC haplotypes for mating that recapitulates the
natural heterogeneity between analogous maternal–paternal
Ags in human pregnancy, circulating maternal CD25+ or
Foxp3+ CD4+ T cells expand significantly above background
levels within 2 d after pregnancy and reach peak ∼2-fold–
enriched levels by midgestation (65, 69, 71, 74). At early
pregnancy time points, immune-suppressive cytokines present
in seminal fluid alone may foster local Treg expansion (75).
Reciprocally for abortion-prone matings among defined
strains of inbred mice (e.g., DBA/2J [H2d] ♂ 3 CBA/J [H2k] ♀),
maternal Tregs are sharply reduced to levels comparable to or
below those found in nonpregnant controls (67). Additional
comparisons using inbred mice with identical or discordant
MHC haplotypes illustrate a direct correlation between the
magnitude of maternal Treg expansion and degree of mismatch between maternal–paternal alloantigens. For example,
maternal Treg expansion is eliminated or diminished to nonsignificant differences during syngeneic pregnancy among
genetically homogenous mice in which the only potential
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CD25
CD25+
CD25high
CD25high
CD25high
CD25high
CD127low CD25high
CD25+
CD25+
CD25high
CD25high
CD25high
CD127low CD25high
CD25+
CD25+
CD25+
CD25high
CD25high
CD127low CD25high
CD25high
CD25high
FOXP3+ 6 (CD252 or CD25high)
CD25high
CD25+ 6 (FOXP3+ or CD127low)a
Fold Change Compared with Nonpregnant
4952
BRIEF REVIEWS: Tregs AND MATERNAL–FETAL TOLERANCE
Table II. Maternal Treg shifts during human pregnancy complications
Condition
Preeclampsia
Spontaneous abortion
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
PBL
Decidua
PBL
Decidua
PBL
Decidua
PBL
PBL
PBL
Decidua
PBL
Decidua
PBL
PBL
Decidua
PBL
Decidua
Decidua
PBL
PBL
+
CD25
CD25high
FOXP3+
CD25high
CD127low CD25high
CD25high
FOXP3+ CD25high
FOXP3+ CD252
FOXP3+ CD25+
CD25+ 6 (FOXP3+ or CD127low)b
CD25high
CD25high
FOXP3+
CD25+
FOXP3+
FOXP3+ CD25+
FOXP3+ CD25+
CD25high
CD25high
CD25high
CD25high
FOXP3+
FOXP3+
CD25high
CD25+
CD25high
CD25high
CD25high
CD25high
FOXP3+ CD25+
CD127low CD25+
CD127low CD25+
CD127low CD25+
FOXP3+ CD25+
FOXP3+ CD25high
FOXP3+
Fold Change Compared with
Uncomplicated Pregnancy
Ref.
1.2 (NS)
0.4 (p , 0.0001)
0.7 (p , 0.001)
0.7 (p , 0.001)
0.8 (p , 0.01)
0.5 (NS)
0.6 (p , 0.001)
0.7 (p , 0.001)
0.7 (p , 0.0001)
Decrease (p , 0.05)
2.4 (NS)
0.5 (p , 0.01)
0.5 (p , 0.01)
1.1 (NS)
0.7 (p = 0.025)
0.7 (p = 0.002)
0.6 (p , 0.05)
0.3 (p , 0.0001)
Decrease (p , 0.001)
Decrease (p, 0.05)
Decrease (p , 0.05)
Decrease (p, 0.05)
0.7d (p = 0.046)
0.8d (p = 0.007)
0.9d (p = 0.0001)
0.4 (p , 0.01)
0.6 (p , 0.01)
0.5 (p , 0.01)
0.6 (p , 0.05)
0.8d (p = 0.03)
0.4 (p , 0.01)
0.7 (p , 0.01)
0.7 (p = 0.005)
0.7 (p = 0.003)
0.6 (p , 0.05)
0.8d (p , 0.05)
(23)
(29)
(31)
(31)
(31)
(32)
(33)
(33)
(36)
(38)
(46)
(47)
(48)
(48)
(49)
(53)
(57)
(26)
(26)
(30)
(30)
(58)
(17)
(17)
(17)
(27)
(27)
(50)
(50)
(51)
(52)
(52)
(54)
(54)
(55)
(56)
a
Gated on CD4+ cells.
Restricted to Helios2 cells.
c
Defined as two or more successive early spontaneous abortions (before 20th week of gestation) of unexplained etiology.
d
Compared with healthy nonpregnant women.
CD25high = CD25bright.
PBL, peripheral blood lymphocyte.
b
source of antigenic mismatch are those encoded by the Y
chromosome, whereas it is consistently more robust in allogeneic pregnancies among MHC haplotype–discordant mice
(35, 70, 71, 73). Thus, although female reproductive hormones and seminal fluid participate in pregnancy preparation
and early pregnancy (17–21, 75), the more robust Treg taccumulation during allogeneic pregnancy compared with
syngeneic pregnancy highlights the additive or potentially
synergistic contribution of maternal–fetal antigenic discordance.
Applying Ag-specific tools to track CD4+ T cells demonstrates even more pronounced accumulation of maternal
Tregs with fetal specificity (72, 73, 76, 77). Using female
mice with fixed TCR specificity or repopulated with donor
monoclonal T cells for breeding showed that pregnancy
stimulates induced Foxp3 expression among CD4+ T cells
with specificity to naturally occurring fetal alloantigens or
OVA expressed as a surrogate fetal Ag (73, 76). Similarly,
when male mice that ubiquitously express the I-Ab 2W1S55–68
peptide were used for breeding with nontransgenic females,
endogenous maternal Tregs with surrogate fetal-2W1S specificity, recovered systemically from the spleen and peripheral lymph nodes, expanded 72-fold compared with bulk
maternal Tregs that expanded ,2-fold (71, 77). Although
the exact molecular and cellular modifications that drive
induced Foxp3 expression and expansion of Tregs with
fetal specificity remain incompletely defined, essential clues
likely reside within decidual maternal APCs stimulated
by fetal components that prime tolerogenic, as opposed to
activated, effector T cell phenotypes (4, 78). A recent study
showed thymic stromal lymphopoietin produced by trophoblast cells markedly augments the capacity of dendritic
cells to induce FOXP3 and CD25 expression among CD252
CD4+ human decidual cells (63). These protective benefits
of qualitative shifts in maternal Tregs are consistent with
the reinstatement of healthy pregnancy by donor Tregs
from pregnant, but not virgin, control mice in abortionprone matings between DBA/2J ♂ 3 CBA/J ♀ mouse
strains (67). Thus, Tregs expand with comparable tempo
and magnitude during uncomplicated human and allogeneic
mouse pregnancy, whereas naturally occurring complications in both species are associated with blunted accumulation of these cells. In turn, mouse pregnancy studies
further uncovered that Treg expansion likely represents
a more focused response toward immunologically foreign
fetal Ags.
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Recurrent spontaneous abortionc
Treg Markera
Source
The Journal of Immunology
4953
Table III. Maternal Treg shifts in mouse pregnancy models
Allogeneic pregnancy
E0–E6.5
E7–E14
Spontaneous abortion
E7 – E14
Syngeneic pregnancy
E0–E6.5
E7–E14
Treg Markera
Treg % Compared with
Nonpregnant
Ref.
BALB/c ♂/♀ 3 CBA/J ♀/♂
B6 ♂ 3 BALB/c ♀
B6 ♂ 3 BALB/c ♀
B6 ♂ 3 CBA/J ♀
CBA ♂ 3 B6 ♀
BALB/c ♂ 3 B6 ♀
CD25+
Foxp3+
CD25+ or Foxp3+
CD25+ or Foxp3+
CD25+
CD25+ or Foxp3+
Increase
Increase
Increase
Increase
Increase
Increase
(68)
(72)
(35, 69, 72)
(68)
(65)
(71)
DBA/2J ♂ 3 CBA/J ♀
CD25+ or Foxp3+
Decreaseb
(67, 68)
Increase
No change
Increase
No change
No change
Increase
Increase
No change
No change
(73)
(73)
(65)
(70)
(72)
(35, 69)
(65, 66)
(69–71)
(72)
B6 ♂ 3 OT-II ♀
B6 ♂ 3 OT-I ♀
B6 ♂ 3 B6 ♀
B6 ♂ 3 B6 ♀
BALB/c ♂ 3 BALB/c ♀
BALB/c ♂ 3 BALB/c ♀
B6 ♂ 3 B6 ♀
B6 ♂ 3 B6 ♀
BALB/c ♂ 3 BALB/c ♀
+
Foxp3
Foxp3+
CD25+
Foxp3+
Foxp3+
CD25+
CD25+/high
CD25+ or Foxp3+
Foxp3+
a
Gated on CD4+ cells.
Compared with nonabortion-prone allogeneic pregnancies.
b
Pregnancy outcomes after maternal Treg manipulation
The protective necessity for maternal Tregs is reinforced by
evaluating pregnancy outcomes after experimental Treg manipulation. In pioneering studies by Aluvihare et al. (65),
depletion of CD25+ cells among donor lymphocytes was
shown to induce fetal wastage after transfer into T cell–deficient female recipients prior to pregnancy. Interestingly, even
in these initial experiments, the necessity for maternal Tregs
linked with immunologically distinct fetal Ag was shown,
because resorption observed in allogeneic pregnancies was
eliminated in syngeneic matings (65). Directly manipulating
Tregs with anti-CD25 Ab administered to pregnant mice
showed that Treg depletion in early pregnancy (embryonic
day [E]2.5) caused implantation failure, whereas depletion
later (E4.5 or E7.5) induced fetal wastage (69, 74). Similar
results were obtained using transgenic mice that coexpress the
high-affinity human diphtheria toxin receptor with Foxp3,
which bypasses potential limitations associated with manipulating Tregs based on CD25 expression. Targeted ablation of
maternal Foxp3+ cells was shown to induce near complete fetal
resorption in allogeneic pregnancy that also became significantly
reduced in syngeneic matings (71, 77). Therefore, although
diphtheria toxin–induced apoptotic cell death may cause inflammation that contributes to these detrimental outcomes (79–
81), the consensus that selectively eliminating Tregs, regardless of
experimental approach, triggers fetal wastage illustrates an essential protective role for these cells (65, 69, 74, 80).
Exploiting the X-linked inheritance of foxp3 and random
inactivation of this chromosome that renders only one-half of
Tregs susceptible to ablation in Foxp3DTR/WT heterozygous
females showed that even partial transient Treg depletion
causes fetal resorption associated with expansion and IFN-g
production by fetal-specific maternal effector T cells (71, 77).
Considering that the maternal Treg nadir reaches prepregnancy levels after depletion in Foxp3DTR/WT mice, which
directly parallels their blunted expansion in naturally occurring human pregnancy complications (Table II), it is likely
that the sustained accumulation of maternal Tregs is required
for maintaining allogeneic pregnancy. Furthermore, the selective loss of male pups with partial Treg depletion in syngeneic pregnancy indicates that the protective benefits of
maternal Tregs are likely not limited to MHC haplotype Ags
and may extend to minor maternal–fetal discordant alloantigens as well (70, 82).
More recent studies with secondary fetal Ag stimulation
further highlight protection by maternal Tregs with fetal
specificity. Using MHC class II tetramers to track CD4+
T cells with the aforementioned I-Ab 2W1S55–68 surrogate
fetal specificity, maternal Tregs with this specificity were
retained at enriched levels postpartum and re-expanded with
accelerated tempo following fetal-2W1S restimulation in
subsequent pregnancy (77). Remarkably, with this enriched
retained pool of fetal-specific memory maternal Tregs, secondary pregnancy becomes markedly more refractory to partial
ablation of bulk Foxp3+ cells, suggesting enhanced protection
by Tregs with fetal specificity. These findings provide critical
immunological clues to explain the partner-specific protective
benefits conferred by prior pregnancy against complications,
such as preeclampsia, in subsequent pregnancies (77, 83).
However, considering that human epidemiological analyses
also showed that these protective benefits wane as the interpregnancy interval becomes significantly extended (84, 85),
a gradual decline in Treg memory that parallels diminishing
numbers of effector CD4+ T cells with time after Ag elimination is predicted (86–88). Thus, establishing the durability
and potential for amplifying the protective properties of maternal Tregs, analogous to booster vaccines for enhancing immunity against pathogens, represents an important area for
translational application of memory Tregs.
Using a complementary approach, other recent studies
also showed that stimulation, under conditions that block
pregnancy-induced Treg expansion among maternal CD4+
T cells with fetal-2W1S specificity, causes a selective loss of
2W1S+ offspring in pregnancies sired by 2W1S-expressing
males (89). This reduction in offspring that occurs in an
Ag-specific fashion parallels similar results with preconceptual
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Model
4954
Conclusions
Although pregnancy represents a ubiquitous model of immune
tolerance, the molecular and cellular alterations required for
sustaining fetal tolerance have remained enigmatic. With the
seminal discovery of Tregs as a unique CD4+ T cell lineage
dedicated to immune suppression, their necessity in averting
autoimmunity and maintaining tolerance to self and “extended-self” commensal Ags swiftly ensued. In parallel, a
compelling complement of human and animal data have
collectively illustrated that the necessity of immune suppression by Tregs extends to maintaining fetal tolerance. Given
the importance of reproductive fitness in species survival, it
also can be argued that the advantages gained from more
prolonged in utero fetal development were a dominant factor
in positive selection that endowed CD4+ T cells with induced
Foxp3 expression to encompass immunologically foreign fetal
Ags. This more prominent consideration of reproductive
success driving stepwise gains in Treg suppression is supported by comparative genomic analyses across species, illustrating conservation within foxp3 compared with associated
enhancer elements (76, 96). For example, although foxp3 is
stringently conserved in mammals, the conserved noncoding
sequence 1 enhancer required for induced Foxp3 expression is
present only in placental mammals and is distinctively absent
in egg-laying monotremes and most marsupial species (76).
This capacity for enhanced accumulation of maternal Tregs
with fetal specificity among eutherian placental mammals
protects against maternal–fetal conflict, allowing more prolonged in utero fetal development; therefore, it likely played
preeminent roles in species selection and survival (76). Based
on this assertion, establishing how Tregs work during pregnancy has both direct translational implications for improving
maternal–fetal health and enormous potential for uncovering
the fundamental biology for how immunity against extended
self-Ags and foreign Ags is regulated. Considering that shifts
in maternal Tregs that establish their underlying importance
in the reproductive process was first described only 10 years
ago, we are enthusiastically optimistic that further investigation in this exciting area will soon unveil the keys to more
comprehensively unlock the enigma of fetal tolerance and
pregnancy complications.
Disclosures
The authors have no financial conflicts of interest.
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BRIEF REVIEWS: Tregs AND MATERNAL–FETAL TOLERANCE
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BRIEF REVIEWS: Tregs AND MATERNAL–FETAL TOLERANCE