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Annu. Rev. Immunol. 2013. 31:387411 Keywords

First published online as a Review in Advance on decidua, pregnancy, leukocyte, immune privilege
January 3, 2013

The Annual Review of Immunology is online at Abstract

immunol.annualreviews.org
The immune cells that reside at the interface between the placenta and
This articles doi:
uterus are thought to play many important roles in pregnancy. Recent
10.1146/annurev-immunol-032712-100003
work has revealed that the composition and function of these cells are
Copyright  c 2013 by Annual Reviews.
locally controlled by the specialized uterine stroma (the decidua) that
All rights reserved
surrounds the implanted conceptus. Here, I discuss how key immune
cell types (natural killer cells, macrophages, dendritic cells, and T cells)
are either enriched or excluded from the decidua, how their function
is regulated within the decidua, and how they variously contribute to
pregnancy success or failure. The discussion emphasizes the relation-
ship between human and mouse studies. Deeper understanding of the
immunology of the maternal-fetal interface promises to yield signicant
insight into the pathogenesis of many human pregnancy complications,
including preeclampsia, intrauterine growth restriction, spontaneous
abortion, preterm birth, and congenital infection.

387
 IY31CH14-Erlebacher ARI 25 February 2013 14:45

INTRODUCTION The implication of this link is that several im-

portant complications of human pregnancy, in-
Reproductive success in placental (eutherian)
cluding recurrent spontaneous abortion (RSA),
Decidua: the mammals depends upon the developmentally
specialized preterm birth, intrauterine growth restriction
and physiologically coordinated interaction
endometrial stromal (IUGR), and preeclampsia, have a developmen-
of two distinct yet physically opposed organ
tissue surrounding the tal component that originates from within the
systems: the placenta and the uterus. The
conceptus; its stromal uterine stroma but becomes evident through
constituents are placenta functions as the primary nutrient and
the action of decidual leukocytes.
decidual stromal cells gas exchange organ of the fetus by diverting
derived from Given my focus on the intrinsic immuno-
maternal blood ow from the uterus. Once
endometrial broblasts logical characteristics of the pregnant uterus, I
inside the placenta, maternal blood exchanges
Preeclampsia: a refrain from discussing work on systemic im-
nutrients, gases, and metabolic waste products
complication of human mune disease and adverse pregnancy outcomes
with fetal blood coursing through a physically
pregnancy associated (e.g., the antiphospholipid antibody syndrome),
separate vasculature that connects to the fetus
with a severe maternal
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org

ways that inammation contributes to implan-

hypertensive syndrome via the umbilical cord. The uterus provides a
tation, ways that bidirectional leukocyte traf-
rich source of blood vessels and a cellular sub-
Fetomaternal cking across the placenta affects the fetal and
tolerance: the stratum (the decidua) that allows the placenta
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maternal immune compartments, and mecha-

seemingly paradoxical to co-opt maternal blood ow in a fashion that
ability of the fetus and
is hemostatically sustainable throughout the
placenta to avoid
length of gestation.
rejection by the
Interactions between the stromal and
maternal immune
system vascular components of the placenta and uterus
do not take place in isolation but rather are
Trophoblasts:
extraembryonic subject to a superimposed layer of regulation
epithelial cells that by the maternal immune cells that populate
compose the bulk of
the decidua. The composition and function of
the placenta and
these cells are highly specialized not only to
replace maternal
foster placental development and function but
endothelial cells in
remodeled spiral also to minimize the chances that the placenta
arterioles is attacked as a foreign organ transplant.
In addition, immune cells exist within the
decidua to combat infection. Here, I discuss
the immunology of the maternal-fetal interface
from the perspective of these diverse sets of
demands, which, as we shall see, may not
always be compatible with one another.
The review rst covers the respective func-
tions of the two major cell types of the maternal-
fetal interface, i.e., natural killer (NK) cells and
macrophages. I will then discuss the behavior
of dendritic cells (DCs) and T cells, given their
importance in host defense and graft rejection,
as well as work on pregnancy immunology from
the perspective of infectious disease control. A
major theme of the review is the emerging link
between immune cell composition and function
at the maternal-fetal interface and the intrinsic
developmental characteristics of the decidua.
nisms of fetomaternal tolerance except as they
relate to immune cell behavior at the maternal-
fetal interface. The reader is referred to several
excellent reviews of these topics (16). I also
refrain from discussing the many immunoreg-
ulatory gene products expressed by cells at the
maternal-fetal interface unless the functional
signicance of their intrauterine expression per
se has been established by in vivo data.
HISTORICAL PERSPECTIVE AND
CLINICAL SIGNIFICANCE
Interest in the immunology of pregnancy
was originally inspired by the realization
that expression of paternal histocompatibility
antigens by the fetus and placenta should
provoke the same kind of tissue rejection
response seen following organ transplantation
(7). The immunological paradox of pregnancy
continues to fascinate both immunologists
and reproductive biologists, and ongoing work
on the problem over several decades has led
to many important discoveries regarding the
systemic immune alterations that occur during
pregnancy and the intrinsic immunological
properties of placental trophoblasts (5, 8).
About 25 years ago, however, the realization
that the leukocytic composition of both the
mouse and human decidua was dominated by an

388 Erlebacher
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
unusual kind of NK cell suggested that decidual
leukocytes might perform key developmental
functions. This possibility was substantiated by
work in mice showing that decidual NK (dNK)
cells play a major role in the massive degree of
uterine vasculature remodeling that takes place
during early gestation, a process that is critical
for the efcient diversion of uterine blood
ow through the placenta. Further work then
established that impaired dNK cell activation
in humans is associated with preeclampsia, an
important obstetrical complication affecting
57% of all pregnancies. These results solid-
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
ied the importance of decidual leukocytes in
human disease.
Another major research avenue, pursued by
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placental pathologists, has been to correlate
various complications of human pregnancy
with specic immunological histopathologies
of the placenta and decidua. A major challenge
with this approach has been to distinguish
between immunological lesions that are un-
derlying causes of pregnancy complications
and those that are secondary to such complica-
tions. In this regard, the relationship between
work in rodents and humans merits some
initial comment, as the synergy of the dual
mouse/human approach that has characterized
key advances in many areas of medicine may
not be so forthcoming in the case of pregnancy.
The concern here is that mouse and human
pregnancy, although similar in some ways (e.g.,
a hemochorial mode of placentation and the
decidual accumulation of NK cells; reviewed
in 8, 9), are also quite different in other, poten-
tially key respects. In addition to the obvious
disparities in placental anatomy and gestational
length (20 days versus 9 months), a critical
difference is that placental trophoblasts do not
invade deeply into decidual arterioles in mice,
whereas they temporarily replace maternal
endothelial cells all the way to the supercial
layers of the myometrium (the smooth muscle
of the uterus) in humans. As a result, the limited
trophoblastic invasion of maternal arterioles
that characterizes preeclampsia and IUGR
could not occur in mice. Other species-specic
differences, immunological or nonimmuno-
logical, might lead to different pathogenic
mechanisms of spontaneous abortion and
preterm birth. Thus, as I discuss what is known
Decidual natural
about various immune cell populations of killer (dNK) cells:
the maternal-fetal interface and their roles specialized NK cells
in both mouse and human pregnancy, I will that represent the
also comment upon the key similarities and majority of all decidual
leukocytes; play a
differences between these populations.
major role in decidual
spiral arteriole
remodeling
THE MATERNAL-FETAL
INTERFACE: AN OVERVIEW OF
ITS DEVELOPMENT AND
IMMUNE CONSTITUENTS
The maternal-fetal interface is the interface be-
tween the uterine mucosa and the extraembry-
onic tissues of the developing conceptus (re-
viewed in 10, 11). Trophoblasts constitute the
primary cell type of these extraembryonic tis-
sues, which on one side of the conceptus form
the placenta and on the other side of the con-
ceptus contribute to the chorioamniotic mem-
brane. The uterine mucosa is not a passive
player in embryo implantation but rather un-
dergoes a specialized tissue reaction termed de-
cidualization to support the development and
function of the placenta (reviewed in 12, 13).
Decidualization entails a radical differentiation
program in endometrial broblasts associated
with changes in cell morphology and gene
expression. In humans, decidual changes oc-
cur to some extent throughout the entire en-
dometrium during the secretory phase of the
menstrual cycle, even in the absence of implan-
tation, but become full blown in early gestation;
in mice, decidualization occurs in response to
implantation and only at implantation sites.
The immune cell constituents of the
maternal-fetal interface are thus the mater-
nal immune cells that populate the decidua
(see Figure 1). Both ow cytometric and tis-
sue immunostaining studies have shown that
rst-trimester human decidual leukocytes are
primarily NK cells (70%) and macrophages
(20%) (reviewed in 14, 15). T cell propor-
tions are more variable (1020%), and DCs,
B cells, and NKT cells are rare. NK cells
are also the dominant leukocyte population of
www.annualreviews.org Biology of Decidual Leukocytes 389
 IY31CH14-Erlebacher ARI 25 February 2013 14:45

IL-15
Decidual stromal cell

Endovascular
trophoblast
IL-10
CSF-1
Interstitial trophoblast

Endothelial cell

Apoptotic
endothelial cell

Blood Vascular smooth

flow muscle cell
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org

Apoptotic vascular
smooth muscle cell
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dNK cell

Macrophage

Dendritic cell

T cell

Red blood cell

Toward placenta Toward myometrium

Figure 1
The major cellular constituents of the rst-trimester human decidua, as shown in the context of a remodeling spiral arteriole. In the
rst phase of remodeling, decidual natural killer (dNK) cells and macrophages accumulate around the vessel wall as the vascular smooth
muscle cells and endothelial cells disperse and degenerate. The vessel is then invaded by a subset of extravillous trophoblasts termed
endovascular trophoblasts. Extravillous trophoblasts invade into the decidua from anchoring placental villi (not shown); those
remaining within the decidual stroma are termed interstitial trophoblasts. The cytokines shown are only those whose possible functions
are discussed at length in the text. Respective cellular sources and target cell types have not been denitively established, so the circuitry
shown is fairly speculative.

the mouse decidua, but systematic studies on
relative leukocyte composition have not been
reported. Work in mice has also revealed a
potential complication in determining decid-
ual leukocyte composition by ow cytometry,
namely that some populations are present pri-
marily within the intravascular compartment
rather than the tissue parenchyma. This issue
is probably not so important for NK cells and
decidual macrophages but is clearly relevant
to monocytes (16) and T cells (17). Strikingly,
large numbers of monocytes appear to be ac-
tively retained within the vascular compartment
of the mouse decidua through stable interaction
with specialized endothelial cells that express
cognate adhesion molecules (18). The physio-
logical signicance of this observation is cur-
rently unclear.
NATURAL KILLER CELLS
Differentiation and Phenotypes
In line with their numerical dominance, dNK
cells have been the focus of most of the work on
the immunology of the maternal-fetal interface
(for reviews, see 1922). In humans, the cells

390 Erlebacher
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
rst appear in the secretory endometrium prior
to implantation and are identied by their
CD56bright CD16 cell surface phenotype.
This surface phenotype is characteristic of
10% of peripheral blood NK (pNK) cells;
however, the transcriptional prole of dNK
cells is quite distinct from both CD56bright
CD16 and CD56dim CD16+ pNK cells (which
constitute the other 90% of blood NK cells)
(23). Compared with pNK cells, dNK cells
also express higher levels of a wide variety of
chemokines, cytokines, and angiogenic factors
(21, 22, 24). These results have suggested
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
that recruited or resident NK cell precursors
are locally induced to differentiate into cells
with highly specialized pregnancy-specic
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functions. Consistent with this idea, TGF-
and IL-15, which are both expressed in the
decidua (25, 26), promote the conversion of
CD56dim CD16+ pNK cells to dNK-like cells
(26), while the treatment of NK cells isolated
from the nonpregnant endometrium (eNK
cells) with IL-15 alone upregulates expression
of NKp30 and NKp44, two receptors highly
expressed by dNK cells (27). Although data for
NKp44 expression are controversial (28), these
latter results also suggest that IL-15 expressed
within the uterus not only acts as an NK cell
survival factor and mitogen, as elsewhere in
the body, but also acts instructively.
In mice, dNK cells appear only during preg-
nancy, show an activated, B220+ CD11c+ sur-
face phenotype, and are primarily identied by
their binding to the lectin from Dolichos biorus
(19, 29). IL-15 is critical for their generation, as
the cells are absent in Il15/ mice (30). Impor-
tantly, although IL-15 expression in the mouse
decidua rises and then declines in parallel with
the number of dNK cells (19, 31), suggesting
local action, the key cellular sources of this cy-
tokine and how expression might be regulated
remain unclear. Decidual macrophages express
high levels of IL-15 in both mice and humans
(25, 31, 32); however, dNK cells develop
in macrophage-decient Csf1op/op mice (33).
Thus, IL-15 production by decidual stromal
cells or decidual endothelial cells may be more
physiologically relevant (25, 32). The lineage
relationship between eNK cells and dNK cells
has also remained unclear (19, 27, 34).
Spiral arterioles:
uterine arterioles that
Role in Decidual Vascular Remodeling
are remodeled into
Current evidence suggests that the primary low-resistance,
role of dNK cells is to promote the uterine high-ow vessels that
supply the placenta
vascular changes necessary for maximizing
with maternal blood
maternal blood ow through the placenta.
As mentioned above, these changes involve
transforming the spiral arterioles of the decidua
into high-capacitance, low-resistance vessels
and replacing the endothelium of these vessels
by trophoblasts that have migrated from the
placenta and invaded the decidua (these are
termed extravillous trophoblasts in humans, to
distinguish them from the trophoblast subtypes
that constitute the villous tree of the placenta
proper). Although controversial (35), recent
work in humans indicates that spiral arteriole
remodeling occurs in two distinct phases
(36). The rst phase occurs in the absence of
nearby trophoblasts and entails the disruption
of perivascular vascular smooth muscle cells
(VSMCs), swelling and loss of continuity
of the endothelium, and partial VSMC and
endothelial cell apoptosis. These changes are
associated with the localized accumulation of
dNK cells and macrophages, as discussed be-
low. The second phase involves the migration
of extravillous trophoblasts into the lumen of
the vessel to form a pseudoendothelium and
the almost complete loss of associated VSMCs
and endothelial cells. The diverted blood then
ows into the space surrounding the placental
villous tree, thereby permitting nutrient and
gas exchange between mother and conceptus.
Incomplete spiral arteriolar transformation, at-
tendant with a failure of trophoblasts to invade
into these vessels all the way to the supercial
layer of the myometrium, is thought to lead to
placental underperfusion, which is presumed to
underlie the pathogenesis of both preeclampsia
and IUGR (37). Its manifestation in the case of
preeclampsia is a severe hypertensive maternal
syndrome in the second and third trimesters
with potentially fatal consequences for both
mother and child (38).
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A role for dNK cells in spiral arteriolar re-
modeling was rst demonstrated by Croy and
colleagues using various strains of NK-decient
mice, including completely alymphoid Rag2/
Il2rg/ mice and mice decient in IL-15 (for
review, see 19). The decidual arterioles in these
mice show greatly thickened walls and narrow
lumens that starkly contrast with the thin walls
and dilated lumens present in wild-type mice.
However, decidual arteriolar remodeling could
be rescued in, for example, Rag2/ Il2rg/ KIR and paternal HLA-C was also found to
mice if the mice were previously engrafted
with bone marrow cells from severe combined
immunodeciency (SCID) donors, which bear
NK cells but lack T cells, B cells, and NKT
cells (39). Decidual arteriolar remodeling could
also be rescued in Rag2/ Il2rg/ mice by trophoblastdNK cell interactions as central to
systemic IFN- injection or by engraftment of
bone marrow cells decient in the IFN- recep-
tor, but not by the engraftment of bone marrow
cells decient in IFN- itself. Together, these
results established that dNK cells contribute to
the remodeling of spiral arterioles through their
production of IFN-. IFN- presumably acts
on non-NK cells within the decidua, potentially
including endothelial cells, but exact pathways
have yet to be elucidated. Interestingly, whereas
IFN- production by mouse dNK cells can be
detected in situ (19), IFN- production by hu-
man dNK cells has only been noted after ex vivo
stimulation (40).
In humans, functional evidence for a role of
dNK cells in spiral arteriolar remodeling and
trophoblast invasion comes from the genetic
epidemiological work of Moffett and colleagues
(20). These researchers study how pregnancy
outcome is inuenced by the maternal geno-
type of the killer-cell immunoglobulin-like
receptor (KIR) family, which encodes NK
cell surface receptors, and the fetal alleles of
HLA-C, which encodes the polymorphic class I
molecule HLA-C. Of the three classical HLA I
molecules, HLA-C is the dominant KIR ligand
and the only one expressed by extravillous
trophoblasts (41). Specically, the risk of devel-
oping preeclampsia was found to be increased
when the maternal KIR repertoire lacked
the telomeric region of the KIR B haplotype
392 Erlebacher
(Tel-B) and the fetus possessed a group C2
HLA-C allele (20, 42). This combination is
functionally notable because Tel-B contains
KIR2DS1, which encodes a strong activat-
ing KIR for HLA-C2. Thus, pregnancies
characterized by the lack of maternal Tel-B
but the presence of fetal/placental HLA-C2
should be associated with a strong inhibitory
signal to dNK cells. More recently, this
same inopportune combination of maternal
increase the risk of RSA and IUGR in an
English cohort (43), although, interestingly,
different KIR/HLA-C compound genotypes
were associated with RSA in China and India
(20). Together, these results strongly implicate
successful pregnancy. In support of this idea,
extravillous trophoblasts can modulate dNK
cell phenotypes in vitro (22), and the two cell
types are in close apposition in situ (43).
Provocatively, Madeja et al. (44) recently
found evidence that a parallel set of inter-
actions between dNK cells and trophoblasts
inuence decidual vessel remodeling in the
mouse. Specically, decidual vessels of preg-
nant BALB/c females maximally dilated only
in the presence of a paternally inherited MHC
class I H-2Kb molecule. H-2Kb was expressed
by invasive trophoblasts in close proximity to
dNK cells and skewed their Ly49 receptor us-
age, thus indicating direct interactions between
the two cell types. Maximal decidual vessel di-
latation was in turn associated with greater fetal
and placental weights. Interestingly, however,
the affected vessels were venous sinusoids rather
than spiral arterioles. Thus, one area of future
work will be to see how the decidual vascular
phenotypes seen in BALB/c females mated with
males of different strain backgrounds square
with those seen in pregnant females devoid of
dNK cells, where only defective spiral arteriole
remodeling and hypomorphic decidua have so
far been reported (39). Notably, failure of spi-
ral arteriole remodeling in dNK celldecient
Rag2/ Il2rg/ mice does not impair fetal or
placental growth or lead to fetal or placental hy-
poxia, nor do pregnant Rag2/ Il2rg/ mice
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
show gestational hypertension like that seen in
patients with preeclampsia (45, 46). On the one
hand, these latter ndings may not be so sur-
prising given that endovascular invasion in the
mouse is normally shallow and that deep inva-
sion is therefore not necessary for adequate pla-
cental perfusion in this species. On the other
hand, Doppler microultrasound studies have
demonstrated several maternal and fetal cardio-
vascular changes specic to Rag2/ Il2rg/ primarily regulated by dNK cells but rather
pregnancies, including increased uterine artery
blood ow velocity and maternal cardiac hy-
pertrophy (47). These changes are presum-
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
ably sufcient to compensate for the increased
resistance of the spiral arterioles in pregnant
Rag2/ Il2rg/ mice (46). These researchers used Doppler ultrasound
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Although compellingly supported by the
data, the idea that direct dNK celltrophoblast
interactions modulate spiral arteriolar remod-
eling in humans also presents somewhat of
a paradox because, as discussed above, the
rst phase of this process likely occurs in the
absence of nearby trophoblasts. One possible
explanation is that dNK celltrophoblast
interactions close to the surface of the placenta
generate long-range signals to trigger perivas-
cular dNK cell and macrophage accumulation
deeper within the decidua and hence the
rst phase of vascular remodeling described
above. In support of this idea, Hazan et al. (48)
used an elegant placenta/decidua coculture
model to show that, although the rst phase
of spiral arteriole remodeling indeed requires
the absolute presence of placental tissue, this
tissue could be as far away as 5001000 m
from the remodeling vessels. Alternatively,
given the ability of dNK cells to produce a
variety of chemokines that can attract human
trophoblasts in vitro (24), impaired dNK cell
function might compromise spiral arteriole
remodeling because inadequate numbers of
trophoblasts are recruited to invade the uterine
vasculature. Although attractive, this interpre-
tation is complicated by other work showing
that dNK cells can also inhibit trophoblast
migration in other assays (49). Furthermore,
Soares and colleagues (50) showed that en-
dovascular invasion in rats, which, like in
humans, occurs deep into the decidua, is even
more robust than normal following acute NK
cell depletion. These authors linked this ob-
servation to impaired development of decidual
spiral arterioles earlier in gestation, hypoxia
at the maternal-fetal interface, and HIF-1-
mediated activation of a trophoblast invasive
phenotype. Together, these results suggest
that trophoblast endovascular invasion is not
occurs as a secondary consequence of hypoxia.
An approach recently pioneered by
Cartwright and colleagues (51) will likely yield
further insight into the cellular interactions that
regulate spiral arteriole remodeling in humans.
to divide rst-trimester pregnancies, prior to
their elective termination, into those with low-
versus high-resistance uterine vessels. Func-
tional assays on dNK cells isolated from these
terminations revealed that only those cells
from low-resistance pregnancies were able to
induce VSMC and endothelial cell apoptosis.
Because the persistence of high-resistance
vessels in the rst trimester is predictive for the
development of preeclampsia (52), these data
provide the rst direct functional evidence of
altered dNK cell function in the pathogenesis
of preeclampsia and suggest that dNK cell
induced VSMC and endothelial cell apoptosis
is a key event in spiral arteriole remodeling.
Role in Intrauterine Inflammation and
Abortion
Curiously, dNK cells in both mice and humans
have long been known to possess large numbers
of granules containing cytotoxic molecules such
as perforin and granzymes (19, 21). These ob-
servations raised the question of why dNK cells
do not threaten fetal survival, especially given
the relatively low levels of classical MHC class
I expression by both human and mouse tro-
phoblasts, a situation that should promote NK
cell cytotoxicity according to the missing-self
hypothesis (53). One explanation for this
quandary is that the cytolytic function of dNK
cells is low at baseline and is furthermore
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 IY31CH14-Erlebacher
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ARI 25 February 2013 14:45
inhibited following dNK cell interactions with
nonclassical class I molecules (i.e., HLA-E
and HLA-G) expressed by extravillous human
trophoblasts (20, 21, 54). In contrast, recent
work has suggested that dNK cells might
be embryotoxic under certain circumstances
(5557). In these studies, mice decient
in the immunosuppressive cytokine IL-10
showed high rates of embryo resorption
when intravenously injected with low doses of
lipopolysaccharide (LPS). Embryo resorption
correlated with elevated levels of TNF- and
IL-6 expression within the uterus (55) and
could be prevented by NK cell depletion or
TNF- blockade but, surprisingly, not by
IFN- blockade (56). LPS treatment of Il10/
mice also induced the migration of decidual
and myometrial NK cells toward the placenta
and increased dNK cell cytolytic activity, two
effects that could also be inhibited by TNF-
blockade (56, 57).
The exact pathways interlinking IL-10,
TNF-, dNK cells, and embryo loss remain
unclear (58). IL-10 is highly expressed in the
mouse decidua (59), and major cellular sources
likely include dNK cells and decidual stromal
cells (58, 60). Furthermore, IL-10, in combi-
nation with the classical macrophage growth
factor CSF-1, has recently been shown to in-
duce human monocytes to differentiate into
macrophages with characteristics similar to
those in the decidua (see below). Thus, dNK
cellderived IL-10 might play a role in induc-
ing the differentiation of decidual macrophages
and maintaining them in a noninammatory
state. Whether activated decidual macrophages
reciprocally regulate dNK cell activity is un-
known, although their close physical proxim-
ity to remodeling spiral arterioles in humans
is provocative. Decidua macrophages and dNK
cells have both been previously implicated in
the high rates of spontaneous abortion in CBA/J
female mice mated to DBA/2 males, although
specic mechanisms remain obscure (61). To-
gether, these results highlight a potential role
for overly robust dNK cell activation in hu-
man pregnancy failure, suggest pathways of
dNK celldecidual macrophage interactions,
394 Erlebacher
and raise questions about the potential func-
tions of dNK cells beyond those that regulate
vascular remodeling.
MACROPHAGES
Macrophages are the second most abundant
leukocyte population within the human de-
cidua (20% of total leukocytes) and are
natural candidates for contributing to tissue
remodeling at the maternal-fetal interface,
given their pleiotropic functions in this regard
in virtually all organ systems. Furthermore,
their prominent roles as pathogen sensors and
immune effector cells suggest a central role
in the inammatory response to decidual or
placental infection. Unlike the genetic studies
of dNK cells described above, which have
established clear functional roles, work on
human decidual macrophages has either been
descriptive or relied upon in vitro systems, and
work on rodent decidual macrophages remains
relatively underdeveloped. The biology of
decidual macrophages therefore represents an
open area of research with major implications
for human health.
Phenotypes and Putative Functions
Human decidual macrophages have been
dened primarily by their expression of the
monocyte/macrophage marker CD14. About
10 years ago, it was found that 70% of the
cells have the unusual feature of expressing the
C-type lectin CD209 [DC-SIGN; dendritic
cellspecic intercellular adhesion molecule-3
(ICAM-3)-grabbing nonintegrin] (62, 63). This
marker is typically associated with immature
monocyte-derived DCs but is also expressed by
macrophages in the lung and dermis (64, 65).
CD209+ macrophages also reside within the
nonpregnant uterus, but at three- to fourfold
lower densities (66). Further work also revealed
that decidual macrophages, on aggregate, con-
stitutively produce elevated levels of IL-10 and
are skewed toward an M2-like macrophage
phenotype, i.e., a phenotype associated with
functions in tissue remodeling, scavenging of
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
apoptotic cells, and generation of immuno-
suppressive tissue microenvironments (6770).
Together, these ndings have suggested that
decidual macrophages are a specialized cell type
generated to perform many specic functions at
the maternal-fetal interface. Excellent reviews
have discussed these possible functions on the
basis of the expression prole of the cells and
the known functions of macrophages and their
gene products outside of pregnancy (71, 72).
There has been particular interest in the
possible role of decidual macrophages in
preeclampsia and IUGR, especially given that
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
descriptions of their perivascular accumulation
have directly implicated the cells in the rst
phase of spiral arteriole remodeling (discussed
by Universidad de Navarra on 08/16/13. For personal use only.
above). In further support of this possibility, de-
cidual macrophages, as compared with CD14+
blood monocytes, express elevated levels of
factors likely to promote the remodeling pro-
cess and the clearance of debris and apoptotic
VSMCs and endothelial cells. These include
bronectin, collagen components, matrix
metalloproteinase-9, complement component
C1q, and the scavenger receptor CD163 (48,
67, 73, 74). Many CD209+ macrophages can
also be seen forming conjugates with dNK
cells, which express the CD209 ligand ICAM-3
(63), suggesting a potential direct coordination
of their activities. Interestingly, elevated de-
cidual macrophage densities have been noted
in third-trimester histological specimens from
preeclamptic pregnancies (7578). These data
are controversial, however, as several other
studies have noted no change (7981). More-
over, because preeclampsia has its pathogenic
origins in the rst trimester, causal relation-
ships inferred from late-gestation decidual
pathologies are inherently tenuous. Therefore,
further insight into the role of macrophages in
decidual arteriole remodeling and preeclamp-
sia will likely depend upon the use of Doppler
ultrasound as described above (51) to prospec-
tively identify those rst-trimester elective
termination specimens that would have been
destined to progress to preeclampsia.
Decidual macrophages likely also contribute
to parturition, given their potential to robustly
express proinammatory mediators and the
current thinking that parturition involves
the activation of inammatory pathways in
Acute
the decidua, ultimately stimulating myome- chorioamnionitis: a
trial contraction (reviewed in 82). Decidual condition caused by
macrophage activation might be induced by bacterial infection of
exposure to pathogen-derived molecular pat- the chorioamniotic
membranes; a major
terns, as likely occurs in acute chorioamnionitis
cause of preterm birth
(see below) or as the result of currently unde- and stillbirth
ned endogenous pathways. Both term labor
and idiopathic (i.e., noninfectious) preterm
labor have also been associated with the selec-
tive accumulation of decidual macrophages in
comparison with term birth without labor (i.e.,
elective cesarean section) (83). These results
suggest that labor entails local production
of monocyte (i.e., macrophage precursor)
chemoattractants or macrophage mitogens and
are therefore intriguing given the evidence
that decidual macrophages may themselves be
the key sources of monocyte chemoattractants
(as discussed below). The extent to which the
recruited macrophages are critical for labor
progression is currently unknown. It is also
unclear whether decidual macrophage produc-
tion of IL-10, which is constitutive in the rst
trimester (69, 74), might be reduced late in
gestation to disinhibit decidual inammation.
Importantly, recent work has revealed that
rst-trimester decidual macrophages divide
into two distinct subsets, with CD209 be-
ing one of several markers that can be used
for their discrimination (73, 74). CD209+
macrophages express high levels of CD163,
CD206 (MRC-1; mannose receptor), CD304
(NRP-1; neuropilin-1), and ICAM-3, and they
express low levels of CD11c. Not surprisingly
given their numerical predominance, these cells
show a transcriptional prole similar to that of
total decidual macrophages analyzed in aggre-
gate (74). In contrast, CD209 macrophages
are CD163 , CD206 , CD304 , ICAM-3 ,
and CD11chi , with a transcriptional prole
closer to that of peripheral blood monocytes.
Importantly, neither the CD209 nor CD209+
decidual macrophage transcriptional prole
corresponds precisely to that of in vitro dif-
ferentiated M1 or M2 macrophages, and both
www.annualreviews.org Biology of Decidual Leukocytes 395
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ARI 25 February 2013 14:45
subsets similarly induce proinammatory cy-
tokines such as IL-6 and TNF- upon in vitro
LPS stimulation (74). Surprisingly, CD209
decidual macrophages produce more IL-10 at
baseline as well as after LPS stimulation than do
CD209+ decidual macrophages (74). These re-
sults emphasize the complexity of macrophage
biology and reveal that functions in tissue re-
modeling versus inammation will not be easily
attributable to one or the other subset.
Population Dynamics and
Differentiation
In humans, CD14+ macrophage densities
have been shown to either increase or remain
relatively constant upon transformation of
the endometrium into the decidua (66, 84).
Curiously, endometrial macrophage densities
in mice dramatically decline upon decidual-
ization (8588). The cause for this decline
has recently been elucidated through work
in our lab on the tissue layerspecic control
of macrophage population dynamics in the
pregnant mouse uterus (16). In the segments
of myometrium that overlay each implantation
site, CSF-1 expression levels dramatically
increase compared with those in the nonpreg-
nant uterus. This has the twofold effect of
increasing in situ macrophage proliferation
rates and inducing macrophage expression of
the monocyte chemokine chemoattractants
CCL2 (MCP-1), CCL7 (MCP-3), and CCL12
(MCP-5). These chemokines promote the ex-
travasation of blood-borne monocytes, which
subsequently differentiate into macrophages.
As a result, macrophage densities remain
constant in the myometrium, even though this
tissue layer, like the underlying decidua, is
rapidly growing over the rst half of gestation.
In contrast, CSF-1 expression remains low in
the decidua, in association with low rates of in
situ macrophage proliferation and monocyte
recruitment. Decidual macrophages therefore
do not homeostatically expand to match the
growth of the tissue and so decline in density.
Together, these data demonstrate the im-
portance of local CSF-1 expression levels in
396 Erlebacher
determining tissue layerspecic macrophage
densities in the pregnant mouse uterus. Thus,
the explanation for why macrophage densities
remain relatively constant upon decidualization
in humans might simply be that decidualization
in humans, like myometrial growth in mice, is
associated with increased CSF-1 expression (89,
90). Furthermore, decidual CSF-1 expression
in humans may directly promote the genera-
tion of CD209+ decidual macrophages, as dual
treatment of blood CD14+ monocytes with
a combination of CSF-1 and IL-10 generates
cells with a phenotype quite similar to that of
the CD209+ decidual macrophage subset (73).
The gene expression pattern in cells induced by
this protocol is notably distinct from that seen
following the IL-4/IL-13 treatment of blood
CD14+ monocytes to induce M2 macrophages.
Consistent with elevated CSF-1 activity in
decidua, CD209+ decidual macrophages are
highly proliferative in situ, whereas their coun-
terparts from the nonpregnant endometrium
are predominantly nonmitotic (63, 66). Sim-
ilarly, decidual macrophages express elevated
levels of the CSF-1 target CCL2 as com-
pared with blood monocytes (67, 73). This lat-
ter result supports the hypothesis that decid-
ual macrophage exposure to CSF-1 is a major
mechanism for human local monocyte recruit-
ment. Although the literature is inconclusive,
the major cellular sources of CSF-1 in the hu-
man decidua are likely decidual stromal cells,
dNK cells, and glandular epithelial cells (90
92).
Provocatively, uterine macrophages in the
mouse also divide into two subsets: F4/80+
MHCIIhi and F4/80+ MHCIIlo . These two
subsets differentially express Cd163 and
Mrc1, suggesting that they might represent
mouse analogs of the CD209 and CD209+
macrophage subsets in the human uterus
(16). Moreover, the MHCIIlo subset expresses
high levels of LYVE-1, a marker previously
associated with angiogenic macrophages (93).
Both subsets exist within the undecidualized
uterus at the time of implantation, but the
MHCIIlo subset disproportionately expands
in the growing myometrium relative to the
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
MHCIIhi subset. This expansion is again due
to high local CSF-1 expression levels, which
block conversion of the MHCIIlo subset into
the MHCIIhi subset. Thus, CSF-1 might
act in both the human decidua and mouse
myometrium to promote the appearance
of macrophages specialized for tissue and
vascular remodeling. Interestingly, CD209+
macrophages have recently been shown to
appear in the human myometrium during
pregnancy (94), potentially drawing a direct
parallel to the situation in mice.
These observations raise the teleological
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
question of why high decidual densities of
CD209+ (or related) macrophages would be
important for human but not mouse reproduc-
by Universidad de Navarra on 08/16/13. For personal use only.
tion. This dichotomy, however, may simply be
the evolutionary consequence of the competing
potential for decidual macrophages to both aid
and hinder pregnancy. As discussed above, de-
cidual macrophages not only pose a latent threat
to reproductive success due to their potential
to express proinammatory molecules, but also
appear to contribute to spiral arteriole remod-
eling (at least in humans). If this latter contri-
bution were irrelevant in mice, then this species
would only manifest a downside to maintaining
high numbers of decidual macrophages.
Understanding the role of uterine
macrophages in pregnancy would clearly
benet from more detailed analyses of rodent
models. Csf1op/op mice show defects in ovulation
and implantation, but once pregnant they
show normal fetal and placental weights (85).
Although this phenotype argues against an
absolute requirement for macrophages in
placental development and function, fetal
resorption rates are nonetheless modestly
increased for reasons that are currently un-
known (85). These mice have also not yet been
analyzed with respect to decidual arteriolar
remodeling, which, as discussed above, can
be severely impaired in the mouse without
overt effects on reproductive success. It will
also be of interest to determine whether
Il10/ mice have altered uterine macrophage
population dynamics or phenotypes, given
the recent evidence that IL-10 can promote
the differentiation of human monocytes into
decidual macrophage-like cells (73). The
function of myometrial macrophages is also an
open question.
DENDRITIC CELLS
DCs stationed within peripheral tissues are
key sentinels of the adaptive immune response.
Upon exposure to pathogens and inammatory
stimuli, they migrate via lymphatic vessels to
the draining lymph nodes, where they present
antigens to naive T cells and direct T cell
expansion and polarization. Furthermore, DCs
can modulate effector T cell accumulation and
function within peripheral tissues. Thus, the
rst notable feature of DCs at the maternal-
fetal interface is their scarcity (reviewed in
95). In humans, mature myeloid DCs, which
are identied as CD83+ cells, are present in
sections of rst-trimester decidua at about
15 cells/mm2 (63, 66, 96, 97). Less-mature
DCs, identied as CD205+ cells, are present
at 2 cells/mm2 (97). These densities starkly
contrast with those of macrophages, which are
present in the range of 50100 cells/mm2 in the
rst-trimester decidua (63, 97). CD83+ DCs
are also present in the cycling endometrium, at
densities that range from 3 cells/mm2 in the
proliferative phase to 9 cells/mm2 in the late
secretory phase (66). These data suggest that
full decidualization after the onset of pregnancy
is associated with a decline in CD83+ DC
densities. Myeloid DCs within the decidua
can also be identied by alternative marker
expression proles, and two studies have
identied a minor population of plasmacytoid
DCs with unknown signicance (98100).
A similar loss of DC densities upon decid-
ualization is also evident in the mouse uterus,
where DCs with lymph nodehoming capacity
are collectively identied as cells with a Ly6C
F4/80 MHCII+ CD11c+ surface phenotype
(16, 88). In contrast, DC densities remain con-
stant in the growing segments of myometrium
that overlay each implantation site. Work from
our laboratory has revealed the cause of this
dichotomy to be a radical difference in the
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ARI 25 February 2013 14:45
control of DC population dynamics between
the two tissue layersa difference that closely
parallels that described above for macrophages
(16). Thus, high rates of in situ DC prolif-
eration and DC precursor (pre-DC) recruit-
ment from the blood are apparent within the
growing myometrium but not decidua, which
means that the cells homeostatically expand
only in the former tissue layer. Unlike the
case with macrophages, however, these differ-
ences in population dynamics are only partly
explained by tissue layerspecic differences in
CSF-1 expression levels (16), thus implicating
unknown factors and possibly new pathways for
actively suppressing DC in situ proliferation
and pre-DC recruitment. The pathways that
regulate DC population dynamics in the human
decidua are currently unknown.
What is the teleological reason for low de-
cidual DC densities? Clearly, a paucity of DCs
within a tissue should limit that tissues ability
to initiate adaptive T cell responses in the
draining lymph nodes. In the case of pregnancy,
such a limitation would be benecial from the
point of view of minimizing immunogenic, mi-
gratory DCmediated T cell responses to fetal/
placental antigens (reviewed in 95). Indeed,
a strong evolutionary pressure to minimize
the number of DCs that can migrate from the
decidua to the uterine lymph nodes is further
supported by our recent observation that those
few DCs present within the mouse decidua
are unable to migrate out of this tissue layer
even upon activation (88). This phenomenon,
which we termed DC entrapment, appears
ultimately linked to the fact that both the
mouse endometrium and decidua completely
lack lymphatic vessels. Although the nding
is controversial (101), lymphatic vessel density
appears to be low in the human decidua in
areas close to spiral arterioles (102), suggesting
that many of the DCs closest to extravillous
trophoblasts in humans may also have difculty
homing to the uterine lymph nodes.
Together, these considerations suggest that
a key function of decidualization is to minimize
DC immunosurveillance of the maternal-fetal
interface. The corollary of this idea is that those
398 Erlebacher
few DCs that reside within the decidua perform
no function; they are merely holdovers from
the endometrium at the time of implantation,
where they presumably functioned to survey
the uterine mucosa for pathogens. However,
rst-trimester human CD83+ decidual DCs
possess T cell immunostimulatory capacity in
ex vivo mixed leukocyte reactions and cluster
with T cells in situ (96). Furthermore, myeloid
decidual DCs, identied as CD14 lin HLA-
DRhi CD11c+ cells, produce lower levels of the
T helper 1 (Th1)-skewing cytokine IL-12 than
do their peripheral blood counterparts and
are somewhat more prone to stimulating Th2
responses (99). These results therefore suggest
that decidual DCs might locally present anti-
gen to decidual T cells in ways that minimize
Th1 responses. No direct evidence supports
this idea at present, and only mild changes in
decidual CD83+ DC densities have been noted
in complications of human pregnancy (78,
103). Furthermore, DCT cell interactions in
the mouse decidua have not yet been reported.
The ultimate signicance of intradecidual DC
T cell interactions in normal and pathological
pregnancies therefore remains unclear.
Recent studies also raise the possibility that
decidual DCs, analogously to dNK cells and
decidual macrophages, play a role in decid-
ual tissue remodeling. This idea has come
from work on CD11c-DTR transgenic mice,
in which CD11c+ cells, including DCs, express
the primate diphtheria toxin receptor (DTR)
that renders them ablatable by diphtheria toxin
(DT). In two studies, DT injection in the
peri-implantation period inhibited decidualiza-
tion, which in turn increased embryo resorp-
tion rates (104, 105). The effect was T cell
independent, arguing against a requirement for
uterine DCs to actively tolerize maternal T cells
with fetal/placental specicity. Instead, DC-
ablated mice showed altered decidual angiogen-
esis, which has been variously ascribed to a loss
of DC-derived soluble Flt1 (sFlt1), to a decoy
receptor for the proangiogenic factor VEGF-
A, or to a role for DCs in dNK cell differentia-
tion or survival (104, 105). The contribution of
DCs to decidualization remains controversial,
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
however, as mice genetically decient in the key
DC growth factor Flt3L, and thus lacking virtu-
ally all uterine DCs, do not show obvious repro-
ductive decits (16). Moreover, dNK cells also
express CD11c, as mentioned above (29), which
complicates the interpretation of CD11c-
DTR-based experiments (reviewed in 95).
Of note, decidual CD209+ (CD14+ )
macrophages have also been suggested to serve
as a potential pool of DC progenitors because
combined IL-1, TNF-, IL-6, and PGE2
treatment of CD14+ decidual macrophages
(composed of 5070% CD209+ cells) gener-
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
ates cells with increased CD83 expression and
the ability to stimulate T cell proliferation in a
mixed leukocyte reaction with potency similar
by Universidad de Navarra on 08/16/13. For personal use only.
to that of cytokine-simulated, peripheral
blood monocytederived DCs (63). However,
decidual macrophages, in aggregate, do not
differentiate into DCs when treated with the
standard IL-4/GM-CSF cytokine cocktail used
to generate DCs from blood monocytes (70).
Together, these results suggest that decidual
macrophages have the potential to convert to
DC-like cells. The in vivo circumstances and
physiological signicance of this conversion,
however, are currently unknown.
T CELLS
Phenotypes and Pathological
Associations
Approximately 1020% of leukocytes in the
rst-trimester human decidua are CD3+
TCR+ T cells; 3045% of these cells are
CD4+ T cells and 4575% are CD8+ T cells
(84, 106109; for review, see 110). Scherjon,
Claas, and colleagues (110112) have shown
that 50% of the CD4+ T cells in the decidua
basalis show an activated/memory CD25dim cell
surface phenotype, whereas 40% of the CD8+
T cells show an effector or effector/memory
CD28 cell surface phenotype (110). About
5% of the CD4+ T cells are CD25bright
FOXP3+ regulatory T cells (Tregs) with im-
munosuppressive properties (109111). These
percentages remain relatively constant over the
course of gestation (110, 112, 113). In an anal-
ysis based upon chemokine receptor expression
patterns, Ernerudh and colleagues (109) found
that putative Th2 and Th17 cells comprise only
5% and 2%, respectively, of rst-trimester
decidual CD4+ T cells, whereas Th1 cells sur-
prisingly comprise 530% of the cells. T
cells, CD4 CD8 TCR+ T cells, and NKT
cells are also present in small numbers (110). In
the mouse, CD4+ and CD8+ T cells each com-
prise 3% of all the leukocytes in the E8.5 de-
cidua (P. Nancy & A. Erlebacher, unpublished
data), but data do not exist on subset compo-
sition, activation status, or cytokine expression
proles.
At present, the function of decidual T cells
is largely unknown. T celldecient mice are
not noted to have any reproductive decits,
and trophic functions for decidual T cells, akin
to those ascribed to dNK cells and decidual
macrophages, have not yet been described.
Instead, the cells have been viewed through the
prism of either their potential negative impact
on pregnancy success [CD8+ cytotoxic T
lymphocytes (CTLs), Th1 cells, Th17 cells] or
their ability to attenuate such an impact (Tregs)
(114). In support of this dichotomy, data exist
linking spontaneous abortion and preeclampsia
with decreased proportions of decidual Tregs
(113, 115), spontaneous abortion with elevated
proportions of decidual Th17 cells (116), and,
controversially, RSA with increased decidual
Th1/Th2 ratios (114, 117). A potential role
for inltrating CD4+ and CD8+ T cells in
adverse pregnancy outcome is also suggested
by three interrelated and frequently coexisting
histological pathologies of third-trimester
pregnancies: chronic deciduitis (which affects
the decidua basalis), chronic chorioamnionitis
(which affects the chorioamniotic membrane),
and villitis of unknown etiology (VUE, which
affects the placental villi with frequent involve-
ment of nearby decidual tissue) (see 118120
and references therein). These pathologies
are each noted in about 1020% of clinically
normal pregnancies but are more frequent in
cases of preterm birth and IUGR. Although
infectious agents are considered unlikely,
www.annualreviews.org Biology of Decidual Leukocytes 399
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ARI 25 February 2013 14:45
the cause of these accumulations is currently
unknown.
Antigen Specificity and Trafficking
Importantly, all these associations have fallen
short of establishing a causal role for decidual
T cells in pregnancy pathologies. In cases of
spontaneous abortion and preeclampsia, the
observed changes in decidual T cell subset
proportions are relatively minor. It is also
unclear whether decidual Treg frequencies are
merely proportional to blood Treg frequencies,
which have been observed to change in some
(but not other) studies during the course of
human pregnancy and may become altered in
certain pregnancy complications (see 109 and
references therein). In cases of chronic de-
ciduitis, chronic chorioamnionitis, and VUE,
phenotypes with respect to activation status,
cytokine expression pattern, and regulatory
capacity have not yet been described.
Perhaps most critically, however, under-
standing the role of decidual T cells in normal
and abnormal pregnancy has been limited by
an almost complete lack of insight into how
many of these cells actually have fetal/placental
specicity and thus might locally perform
TCR-mediated effector or regulatory func-
tions. In the only study to address this issue
directly in humans (121), the proportion of
CD25dim (i.e., activated or memory) CD4+
T cells in the decidua of term pregnancies was
mildly (10%) elevated if there was a mismatch
between maternal and fetal HLA-C alleles, but
not if there was a mismatch in HLA-A, -B, -DR
or -DQ (121). Because trophoblasts do not
express MHC-II molecules, this result suggests
that trophoblast HLA-C protein is ingested
and presented by maternal antigen-presenting
cells either in the secondary lymphoid organs
or within the decidua itself. Surprisingly, how-
ever, mother/child HLA-C mismatch did not
correlate with increases in the proportion of
decidual CD28 (effector or effector/memory)
CD8+ T cells (121).
Although this analysis was conned to a
single antigen, it nonetheless suggests that
400 Erlebacher
many decidual T cells might simply lack fe-
tal/placental specicity. In this regard, it is im-
portant to emphasize that the increased acti-
vation marker expression levels (e.g., of CD25
and CD69) characteristic of many decidual T
cells could occur as consequence of cytokine
exposure rather than TCR engagement (122),
and that the reported (e.g., 110) increases in ef-
fector, effector/memory, and regulatory subset
proportions compared with peripheral blood
could have many explanations, including, most
obviously, the much larger proportion of naive
T cells in blood versus tissue. It is also impor-
tant to note that activated T cells can accumu-
late in an antigen-nonspecic fashion at sites
of inammation (123, 124), thus potentially ex-
plaining the accumulations seen in chronic de-
ciduitis, chronic chorioamnionitis, and VUE.
However, the most suggestive evidence for
a lack of fetal/placental specicity for decidual
T cells comes from mouse models in which
the behavior of maternal T cells with known
fetal/placental specicity can be studied in
great detail. These studies have revealed that
naive maternal CD8+ T cells not only fail to
encounter antigen within the decidua (as would
be expected given that naive T cells are mostly
excluded from peripheral tissues) and fail to be
primed upon fetal/placental antigen exposure
in the secondary lymphoid [125 (for CD8+ T
cells); C.-S. Tay & A. Erlebacher, unpublished
data (for CD4+ T cells)], but also fail to
extravasate from the blood to the decidua even
after forced experimental activation and differ-
entiation into Th1 cells and CTLs (17). This
latter result led to the nding that differentiat-
ing decidual stromal cells activate an epigenetic
program that transcriptionally silences ex-
pression of the key Th1/CTL-attracting
chemokines CXCL9 (MIG), CXCL10 (IP-10),
CXCL11 (I-TAC), and CCL5 (RANTES)
even under conditions of systemic inamma-
tion (17). The ability of the decidua to resist
inltration by activated Th1 cells and CTLs
was independent of cognate antigen expression
by the conceptus (17), revealing a dominant
role for decidual stromal cells in the control of
decidual leukocyte composition.
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
Thus, although a great deal more research
is required on this topic, current evidence
predicts that any Th1 cell or CTL found in the
decidua of a normal murine pregnancy will lack
fetal/placental specicity. This prediction even
extends to cases of apparent T cellmediated
fetal loss in mice, because decidual T cell
accumulation in these cases, when documented
(e.g., 126), appears quite limited. Instead, T
cellmediated fetal loss might be a consequence
of T cell action outside the uterus, as discussed
elsewhere (127).
A major question in the eld is thus whether
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
similar restrictions on T cell activation and de-
cidual access apply to human pregnancy, which
in turn would imply that human decidual Th1
by Universidad de Navarra on 08/16/13. For personal use only.
cells and CTLs would also predominantly lack
fetal/placental specicity. Indeed, even rst-
trimester spontaneous abortions are not char-
acterized by decidual T cell inltration, an ob-
servation that stands in stark contrast to the
massive T cell accumulation seen during acute
surgical organ transplant rejection. However, it
remains possible that non-Th1 CD4+ T cells
(Th2, Th17, Treg) in the decidua are spe-
cic for fetal/placental antigens, given that the
recruitment of such cells does not rely upon
CXCL9, 10, or 11 or CCL5. Tregs might even
employ specialized mechanisms to gain access
to the maternal-fetal interface, as suggested by
recent work showing their chemotropism for
human chorionic gonadotropin (hCG), a highly
expressed trophoblast product (128). It is also
of interest that many CD3+ T cells in periglan-
dular leukocyte aggregates of rst-trimester de-
cidua are undergoing apoptosis, a phenomenon
linked in vitro to the effects of Galectin-1, an
immunomodulatory lectin produced by dNK
cells and decidual macrophages (129). Thus, the
direct induction of T cell apoptosis might be yet
another mechanism for limiting T cell accumu-
lation at the maternal-fetal interface and might
selectively enrich for certain T cell subsets.
These possibilities, however, still encounter
the issue of whether fetal/placental-specic
non-Th1 CD4+ cells or CTLs are ever gen-
erated during pregnancy. A recent study ad-
dressing these questions in mice detected
fetal/placental-specic Tregs in implantation
sites; however, the key experiment was per-
formed using mice in which the precursors of
these cells already constituted 100% of the ma-
ternal T cell compartment (126). Moreover,
only a small percentage of the cells (3%) con-
verted to Tregs, and it was unclear how many
of these cells were actually blood contaminants
because the ow cytometric analysis was per-
formed on the combined deciduas and placentas
of E13.514.5 pregnancies, when the placenta
contains a great deal of maternal blood.
Lastly, it remains an open question whether
those T cells that reside within the decidua
have any specic function, even if antigen
nonspecic, or contribute to pregnancy com-
plications in an antigen-nonspecic fashion.
Provocatively, the decidual and peridecidual T
cell accumulations seen with chronic deciduitis,
chronic chorioamnionitis, and VUE suggest
that loss of chemokine silencing in human de-
cidual stromal cells might be a feature of late
gestation pregnancy complications. Consistent
with this idea, CXCL9, 10, and 11 are upreg-
ulated in chorioamniotic membranes affected
by chronic chorioamnionitis, but the cellular
source of these chemokines has not been de-
scribed (118). Another major unresolved ques-
tion is whether the T cells in these lesions are
specic for fetal/placental antigens.
INFECTIOUS DISEASE CONTROL
AT THE MATERNAL-FETAL
INTERFACE
A variety of organisms can infect the placenta
and the chorioamniotic membranes to cause
pregnancy complications such as preterm birth,
IUGR, and stillbirth (130). Fetal infection fol-
lowing transplacental transmission also causes a
range of congenital abnormalities. At least one
organism, Plasmodium falciparum, likely reaches
the villous tree directly via maternal blood and
will not be discussed further. Other organ-
isms rst infect the decidua and then spread to
the placenta via anchoring villi (for review, see
131). Thus, as pointed out by many authors,
the decidua is ground zero for considering how
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ARI 25 February 2013 14:45
requirements for avoiding an immunological
assault on the fetus and placenta conict with
the necessity of protecting them from infection.
Here, I discuss this conict with regards to two
organisms, the herpesvirus cytomegalovirus
(CMV) and the facultative intracellular anaer-
obe Listeria monocytogenes, in which current re-
sults are perhaps most informative. I also touch
upon the pathogenesis of acute chorioamnioni-
tis, which is the major cause of preterm birth
and mainly the result of ascending bacterial
infection from the cervix. Although the con-
tribution of decidual infection per se to acute
chorioamnionitis is not clearly established,
work on this pregnancy complication is provid-
ing insight into the host defense mechanisms
that operate at the maternal-fetal interface.
Cytomegalovirus
CMV latently infects 3070% of the popu-
lation (132). Hematopoietic progenitors and
mononuclear phagocytes serve as a major cel-
lular reservoir in humans, but work on mouse
CMV has suggested that the virus also per-
sists in the stromal cell compartment at a vari-
ety of anatomical locations (133). In immuno-
competent hosts, local viral reactivation is
thought to be a frequent occurrence quickly
controlled by a large pool of memory T cells
(133). Clinically signicant disease is there-
fore typically apparent only in organ trans-
plant recipients and HIV-infected individuals.
It is therefore remarkable that, in a seminal
study by Pereira, Fisher, and colleagues (134),
CMV DNA could be detected in the decidua
of 89% of rst-trimester elective terminations
performed for nonmedical reasons. Moreover,
13 of the 23 decidua analyzed further showed
positive intracellular staining for infected cell
proteins, indicative of active viral replication
(134). The staining was patchy and was ob-
served in uterine epithelial cells, decidual stro-
mal cells, and endothelial cells. In the remain-
ing 10 samples, the viral coat protein gB was
detectable in DC-SIGN+ macrophages, con-
sistent with nearby virus production. CMV
DNA was more frequently detectable in decid-
402 Erlebacher
ual biopsies compared with placental biopsies
from the same specimen, suggesting that in-
fection progresses from the decidua to the pla-
centa. Provocatively, the degree of placental in-
fection negatively correlated with maternal IgG
neutralizing antibody titers (135). While this
result demonstrated that viral reactivation (high
antibody titers) was less severe than primary in-
fection (low antibody titers), it was also surpris-
ing because viral spread following reactivation
is thought to be primarily controlled by T cells.
Indeed, areas of decidual CMV infection do not
contain prominent T cell accumulations (136).
Together, these observations raise the possibil-
ity that active CMV infection of the decidua oc-
curs at a high rate because T cells cannot gain
access to this tissue. As a result, humoral im-
munity might be the only defense available to
control virus spread to the placenta and fetus.
Listeria monocytogenes
As with CMV, L. monocytogenes infection is ul-
timately controlled by T cells (137). L. mono-
cytogenes was historically thought to infect the
human placenta directly via the blood; how-
ever, recent work has demonstrated that syncy-
tiotrophoblasts, which in humans compose the
outer layer of placental villi in direct contact
with maternal blood, are quite resistant to di-
rect infection (138). Instead, the organism ap-
pears to spread from extravillous trophoblasts
in the decidua through the anchoring villi to
access the body of the placenta, a pathway that
can be recapitulated in placental organ culture
(138). This pathway parallels the decidua-to-
placenta route of infection thought to occur in
mice (139). How L. monocytogenes accesses the
decidua in the rst place is currently unclear,
but it has been speculated that the organisms are
carried by extravasating leukocytes (131). Once
colonized, the decidua and placenta act as a ma-
jor reservoir for the organism that, in mice and
guinea pigs, can continuously seed the rest of
the mothers body despite the organisms active
clearance outside the uterus (140). Earlier work
in mice further demonstrated that decidual L.
monocytogenes infection is not associated with
T cell accumulation (139), consistent with our
 IY31CH14-Erlebacher ARI 25 February 2013 14:45
work on decidual chemokine silencing, and that
pregnancy per se does not compromise systemic
antilisterial responses (141). It therefore ap-
pears that the immunoprivileged environment
provided by the decidua, at least with respect to
T cellmediated immunity, allows for the local
survival of L. monocytogenes as it does for CMV.
The decidua does not, however, appear to
be completely at the mercy of pathogens that
require T cells for clearance. In the case of
L. monocytogenes, recent work suggests that
macrophages represent one component of this
innate resistance mechanism, as macrophage-
Annu. Rev. Immunol. 2013.31:387-411. Downloaded from www.annualreviews.org
decient Csf1op/op mice and mice subjected to
acute macrophage ablation both show much
higher decidual L. monocytogenes titers following
by Universidad de Navarra on 08/16/13. For personal use only.
the intravenous injection of low doses of bacte-
ria (59). The relevant macrophages appear to be
those few present within the decidua at baseline,
because uterine infection induces macrophage
recruitment solely to the myometrium and sub-
myometrial stroma (59). Neutrophils are also
recruited to the decidua in the course of L.
monocytogenes infection (139), but their rele-
vance remains poorly understood. In humans,
extravillous trophoblasts also show an innate re-
sistance to L. monocytogenes and are able to kill
the organism via intracellular pathways (142).
Of interest, these cells also express the CSF-1
receptor (143).
Acute Chorioamnionitis
Neutrophils are by far the predominant leuko-
cyte recruited to the chorioamniotic membrane
in acute chorioamnionitis. This is not sur-
prising, given that acute chorioamnionitis is
caused by bacterial infection. Open questions,
however, include the exact pathways that
mediate neutrophil recruitment and whether
these pathways are limited by the intrinsic
characteristics of the maternal-fetal interface.
Several studies have shown that the neutrophil
chemoattractant IL-8 and a variety of Toll-like
receptors are expressed by human decidual
stromal cells, trophoblasts, and amniotic
epithelial cells (144; reviewed in 145, 146), and
these factors are also expected to be expressed
by decidual leukocytes. Thus, it is likely that IL-
8 is directly induced upon bacterial infection.
However, neutrophil recruitment to mucosal
sites is thought to be maximized by the syner-
gistic action of IL-17, which is predominantly a
T cell product, and IL-22, which is made by in-
nate lymphoid cells (147). These cytokines act
on epithelial cells to induce high levels of neu-
trophil chemoattractants (i.e., IL-8 in humans;
CXCL1, 2, and 5 in mice), neutrophil survival
factors (G-CSF), and a range of bactericidal
agents. Investigations into the roles of these
pathways in acute chorioamnionitis are only
beginning to be performed. In one recent study,
Saito and colleagues (148) showed that acute
chorioamnionitis was associated with increased
IL-17 levels in the chorioamniotic uid and the
accumulation of IL-17-producing Th17 cells
in the chorioamniotic membrane. In another
study of acute chorioamnionitis, amniotic uid
levels of CCL20, the inammatory chemokine
responsible for attracting Th17 cells, were also
elevated, suggesting local CCL20 synthesis as a
possible mechanism for Th17 cell recruitment
(149). Further work along these lines will
likely reveal key pathogenic mechanisms of
this important pregnancy complication.
PROSPECTIVE VIEW: THE
IMMUNOLOGY OF THE
MATERNAL-FETAL INTERFACE
AS A FUNCTION OF DECIDUAL
DEVELOPMENT AND FUNCTION
From an immunological perspective, the de-
cidua has two striking features that optimize
its role in reproduction. The rst is the high
degree of specialization of its resident leuko-
cyte populations, the most obvious examples at
present being CD56bright NK cells and CD209+
macrophages, which are both rare outside the
pregnant uterus. The second is its capacity to
restrict the accumulation of certain immune cell
types. As mentioned, NK cells are the predom-
inant cell type of both the human and mouse
decidua, whereas macrophages are abundant in
the human decidua but not the mouse decidua.
In contrast, T cells, DCs, and especially B cells
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ARI 25 February 2013 14:45
are quite scarce during normal pregnancy in
both the human and mouse decidua. Indeed,
our work in mice reveals that the decidua re-
sists the inltration of even activated Th1 cells
and CTLs that are otherwise capable of promis-
cuously homing throughout peripheral tissues.
Provocatively, the immunological prop-
erties of the decidua appear predominantly
intrinsic to this tissue layer, as they are evident
even in the absence of embryo implantation.
In humans, such a situation occurs at the end
of each menstrual cycle, when spontaneous
decidual changes are associated with NK cell
accumulation. In mice, articial decidual reac-
tions can be experimentally induced by various
intrauterine stimuli (e.g., the intraluminal
injection of sesame seed oil). These reactions
show the same degree of dNK cell accumula-
tion, loss of macrophage and DC density, and T
cell exclusion as true decidua. The autonomy of
the decidua as a developmental system in mice
is perhaps best evidenced by the fact that both
implantation-induced and articial decidual
reactions show the same stereotypical and spa-
tially polarized response, with an NK cellrich
decidua basalis and a leukocyte-poor decidua
capsularis. Furthermore, with few exceptions
(150), a large number of developmental reg-
ulators (morphogens, growth factors, etc.)
show the same spatial and temporal patterns of
expression in both true and articial decidua.
These observations suggest that the devel-
opmental biology of the decidua is ultimately
central to how the maternal immune system in-
uences fetal and placental development. Along
these lines, I have discussed how mouse and
human decidual stromal cells are likely key
DISCLOSURE STATEMENT
The author is not aware of any afliations, memberships, funding, or nancial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
The author would like to thank the members of his laboratory for many stimulating discussions, S.
Ananth Karumanchi for input, and Susan Fisher, B. Anne Croy, Ashley Moffett, Anna Bakardjiev,
404 Erlebacher
IL-15 sources that foster dNK cell survival
and differentiation, how levels of CSF-1 ex-
pression in mouse versus human decidua likely
explain species-specic differences in decid-
ual macrophage population dynamics, and how
chemokine gene silencing in mouse decidual
stromal cells prevents expression of Th1 and
CTL chemoattractants. It is also worth recall-
ing that both the endometrium and decidua
in the mouse uterus are devoid of lymphatic
vessels and that the human decidua shows a
paucity of lymphatic vessels. These decien-
cies, at least in mice, minimize DC surveillance
of the maternal-fetal interface and presumably
reect the inadequate local production of lym-
phangiogenic factors or the local production of
lymphangiogenesis inhibitors. Together, these
observations suggest that global developmental
programs operate within endometrial and de-
cidual stromal cells to coordinate multiple as-
pects of decidual immunology. Although the
molecular components of such programs are
currently unknown, the corollary of this idea
is that their disruption might underlie many
of the ways that the maternal immune sys-
tem contributes to human pregnancy compli-
cations. Such disruptions might have a genetic,
epigenetic, or environmental origin. Given the
importance of decidual immunology for pla-
cental development and function and the in-
creasingly recognized long-term inuence of in
utero events on human health (developmental
programming or the fetal origins hypothesis),
further insight into the immunological proper-
ties of the decidua, and decidual stromal cells
in particular, will likely have a major impact on
human health.
 IY31CH14-Erlebacher ARI 25 February 2013 14:45

Lenore Pereira, Patrice Nancy, and Adam Blaisdell for comments on the manuscript. Work
from the authors laboratory was supported by grants from the National Institutes of Health, the
American Cancer Society, and the Leona M. and Harry B. Helmsley Charitable Trust.

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Annual Review of
Contents Immunology
Volume 31, 2013

Years in Cologne
Klaus Rajewsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
The Biology of Recent Thymic Emigrants
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Immunogenic Cell Death in Cancer Therapy
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Recognition of Bacteria by Inammasomes
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The Immunology of Fibrosis
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Johann Feichtinger, Bettina Zelger, Roswitha Sgonc, and Dolores Wolfram p p p p p p p p p 107
Memory T Cell Subsets, Migration Patterns, and Tissue Residence
Scott N. Mueller, Thomas Gebhardt, Francis R. Carbone, and William R. Heath p p p p p 137
Control of Human Viral Infections by Natural Killer Cells
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Controlling Natural Killer Cell Responses: Integration of Signals for
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Metabolic Regulation of T Lymphocytes
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Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche
and a Stepping-Stone for Regenerative Medicine
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Interleukin-4- and Interleukin-13-Mediated Alternatively Activated
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Brain-Reactive Antibodies and Disease
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v
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Immunology of the Maternal-Fetal Interface

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Regulation of Ligands for the NKG2D Activating Receptor
David H. Raulet, Stephan Gasser, Benjamin G. Gowen, Weiwen Deng,
and Heiyoun Jung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Pathways of Antigen Processing
Janice S. Blum, Pamela A. Wearsch, and Peter Cresswell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
The Immune Response in Tuberculosis
Anne OGarra, Paul S. Redford, Finlay W. McNab, and Chloe I. Bloom,
Robert J. Wilkinson, and Matthew P.R. Berry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 475
The Adaptable Major Histocompatibility Complex (MHC) Fold: Structure
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and Function of Nonclassical and MHC Class ILike Molecules

Erin J. Adams and Adrienne M. Luoma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 529
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The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and
Their Subsets in the Steady State and the Inamed Setting
Miriam Merad, Priyanka Sathe, Julie Helft, Jennifer Miller, and Arthur Mortha p p p 563
T CellMediated Host Immune Defenses in the Lung
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Human Hemato-Lymphoid System Mice: Current Use and Future Potential
for Medicine
Anthony Rongvaux, Hitoshi Takizawa, Till Strowig, Tim Willinger,
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Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells
Klaus Okkenhaug p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 675
Broadly Neutralizing Antiviral Antibodies
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Molecular Control of Steady-State Dendritic Cell Maturation and Immune
Homeostasis
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Cumulative Index of Contributing Authors, Volumes 2131 p p p p p p p p p p p p p p p p p p p p p p p p p p p 793

Cumulative Index of Articles Titles, Volumes 2131 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 800

Errata

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