YALE JOURNAL OF BIOLOGY AND MEDICINE 85 (2012), pp.105-118.
Copyright © 2012.
Decidual Macrophages and Their Roles at the
Brandy L. Houser
Stem Cell and Regenerative Biology Department, Harvard University, Boston,
The semi-allogeneic fetus, whose genome consists of maternally and paternally inherited al-
leles, must coexist with an active maternal immune system during its 9 months in utero.
Macrophages are the second most abundant immune cell at the maternal-fetal interface, al-
though populations and functions for these populations remain ill defined. We have previ-
ously reported two distinct subsets of CD14+decidual macrophages found to be present in
first trimester decidual tissue, 20 percent CD11cHIand 68 percent CD11cLO. Interestingly,
CD11cHIdecidual macrophages express genes associated with lipid metabolism, inflam-
mation, and antigen presentation function and specifically upregulate CD1 molecules. Con-
versely, CD11cLOdecidual macrophages express genes associated with extracellular matrix
formation, muscle regulation, and tissue growth. The large abundance of CD11cHIdecidual
macrophages and their ability to process antigens more efficiently than CD11cLO
macrophages suggests that CD11cHImacrophages may be important antigen processing
and presenting cells at the maternal-fetal interface, while CD11cLOmacrophages may per-
form necessary homeostatic functions during placental construction. Thus, macrophage het-
erogeneity may be an important and necessary division of labor that leads to both an
induction of maternal immune cell tolerance to fetal antigens as well as basic homeostatic
functions in human pregnancy.
To whom all correspondence should be addressed: Brandy L. Houser, Harvard University,
Stem Cell and Regenerative Biology Department, 101 Huntington Avenue, Boston, MA
02115; Tele: 617-999-0213; Fax: 617-954-9361; Email: firstname.lastname@example.org.
†Abbreviations: APC, antigen presenting cell; CD, cluster of differentiation; DC, dendritic
cell; dM!, decidual macrophage; dNK, decidual natural killer cell; EVT, extravillous tro-
phoblast; FACS, fluorescence-activated cell sorting; HLA, human leukocyte antigen; IFN-
, interferon gamma; Ig, immunoglobulin; IL, interleukin; ITAM, immunoreceptor
tyrosine-based activating motif; ITIM, immunoreceptor tyrosine-based inhibitory motif,
KIR, killer Ig-like receptor; LPS, Lipopolysaccharides; MHC, major histocompatability
complex; MR, mannose receptor; PE, phycoerythrin; SA, scavenger receptor; TCR, T cell
receptor; TLR, toll like receptor.
Keywords: pregnancy, reproduction, macrophages, antigen presenting cells, NK cells,
Viviparity, or live birth, has evolved in-
dependently in several species. Eutheria,
from the Greek for “well developed beast,”
are a clade of viviparous mammals in which
the fetus is nourished during gestation by a
placenta . The placenta consists of two
basic elements: an inner vascular network and
an outer epithelium . The outer epithelium,
comprised of trophoblast cells, provides the
main structural and functional components of
the placenta and allows for oxygen and nutri-
ent exchange between mother and child. The
inner vasculature and stroma are derived from
Placentation begins when fetal-derived
trophoblast cells from the recently implanted
blastocyst invade the uterine lining. Simul-
taneously, cells of the endometrium also
begin to prepare for this invasion, in a
process known as decidualization . The
mammalian chorioallantoic placenta is es-
sential for the growth and development of
the fetus and distinguishes Eutherian mam-
mals from other organisms. There are three
main types of Eutherian placentation: ep-
itheliochorial, endotheliochorial, and hemo-
chorial . These distinctions are made
based upon contact between trophoblast
cells and the uterine lining. In epitheliocho-
rial placentation, trophoblast cells can reach
and sometimes fuse with the surface epithe-
lium of the uterus, while in endotheliochor-
ial placentation, trophoblasts can reach the
maternal blood vessels . Humans undergo
hemochorial placentation, wherein fetal
membranes are in direct contact with mater-
nal tissue and blood (Figure 1). This intimate
contact between the fetal-placental unit and
mother was established in the last common
crown group of Eutheria and gives credence
that a successful pregnancy requires appro-
priate allorecognition and tolerance at the
maternal-fetal interface .
THE HUMAN MATERNAL-FETAL
The maternal-fetal interface is a dy-
namic site that encompasses multiple cellu-
lar interactions in an environment rich in cy-
tokines and hormones . During the first
trimester (weeks 1-12 post-fertilization), in-
terstitial and endovascular infiltration of tro-
phoblast cells elicit both the recruitment of
maternal immune cells and the production
of pro-inflammatory cytokines . It is
commonly thought that immune responses
by the mother help to protect from tro-
phoblast over-invasion while allowing for
the acceptance of the semi-allogeneic fetal-
Immunohistochemical staining against
the leukocyte common antigen CD45 has
shown that 40 percent of cells in the decidua
during the first trimester are leukocytes .
An estimated 50 to 60 percent of decidual
leukocytes are CD56brightCD3-NK cells .
The remaining leukocytic infiltrate is com-
prised of roughly 10 percent T cells, 1 to 2
percent dendritic cells (DCs†), and 20 to 25
percent M!s . The decidual macrophage
(dM!) compartment consists of at least two
distinct subsets based upon differential ex-
pression of the complement receptor CD11c
and are now termed CD11cHIand CD11cLO
. Decidual leukocytes at the maternal-
fetal interface play important roles in both
allorecognition of fetal antigens and in the
development of the fetal-placental unit.
IMMUNOBIOLOGY OF REPRODUCTIVE
FAILURE IN HUMANS
Statistically, human pregnancy is re-
markably inefficient. It has been estimated
that approximately 50 to 60 percent of all
human concepti die prior to birth . The
majority of these deaths occur before im-
plantation; however, between 15 and 20 per-
cent of otherwise successful embryo
implants will result in an early spontaneous
abortion [13,14]. Although pregnancy loss
has been attributed to vague complications
such as genetic, endocrinological, and
anatomical abnormalities, the majority of
miscarriages remain unexplained.
Haemolytic disease of the newborn was
the first recognized immunological compli-
cation of human pregnancy . This dis-
ease develops because the mother is
Houser: Decidual macrophages at the maternal-fetal interface
immunized by antigens on fetal erythrocytes
from an earlier pregnancy. This leads to an-
tibody-mediated haemolysis of the fetus in
a subsequent pregnancy. These antigens are
termed “Rhesus factor” (Rh) because early
studies utilized red blood cells from Rhesus
macaques . These data contributed to Sir
Peter Medawar’s development of the con-
cept of maternal tolerance to the fetus, and
he proposed three potential explanations re-
garding why the maternal immune system
does not reject the fetus: physical separation
of mother and fetus, antigenic immaturity of
fetal tissues, and immunological inertness of
the mother [17,18]. However, none of these
three proposed concepts account for mater-
nal tolerance to fetal antigens.
There are now several well-character-
ized immunological factors known to aid in
fetal tolerance, including complement in-
hibitory receptors [19,20], absence of major
MHC expression, expression of non-poly-
morphic non-classical presenting molecules
, and cytokine balance. Although the
fetal-placental unit is often equated to a vas-
cularized allograft, classical allogeneic re-
jection of invading fetal cells is avoided
because of the absence of MHC class II.
However, there are several disorders, in-
cluding tubal pregnancy, placenta accreta,
and preeclampsia, that occur in part due to
immune misregulation .
Preeclampsia occurs in as many as 10
percent of all human pregnancies  and is
107 Houser: Decidual macrophages at the maternal-fetal interface
Figure 1. The Human Maternal-Fetal Interface. A block section of the chorioallantoic
human placenta shows chorionic villous trees in direct contact with the decidua basalis
and the maternal blood supply in order to provide oxygen and nutrients to the growing
fetus. The insert shows HLA-G+extravillious trophoblast cells invading the endothelium
and unwinding the maternal spiral artery, allowing for maternal blood to enter the intervil-
lous spaces. At this site, fetal trophoblast cells come into direct contact with maternal im-
mune cells such as dMs, NK cells, and T cells.
the primary pathogenesis of inadequate inva-
sion of extra-villous trophoblasts (EVT) and
insufficient remodeling of the maternal-spi-
ral arteries [23-25]. This ultimately leads to a
lack of maternal blood flow into the intervil-
lous space and manifests in the mother as pro-
teinuria, edema, and hypertension. Although
other factors have been shown to contribute
to preeclampsia, it is generally thought of as
an immunological manifestation of the mis-
regulation of trophoblast invasion by mater-
nal leukocytes . Further evidence of
immunological involvement in preeclampsia
has been shown in cases where a primipara
who had preeclampsia has a reduced risk with
a change in partner . In addition, in the
case of oocyte donation in which the fetus is
entirely non-self, the risk of preeclampsia is
elevated to 30 percent .
M!s have been shown to play impor-
tant roles in pregnancy maladies, including
preeclampsia. In normal human pregnan-
cies, dM!s are located in the surrounding
stroma and near the spiral arteries; however,
in preeclamptic pregnancies, the dM!s are
mostly located within and around the spiral
arteries and appear to physically inhibit tro-
phoblast remodeling [29,30]. Moreover, it
has been reported through ex vivo studies
that dM!s can limit EVT invasion of spiral
arteries through apoptosis mediated secre-
tion of TNF- [30,31]. In summary, M!s at
the human maternal-fetal interface play im-
portant roles during normal placental devel-
opment, and the misregulation of these cells
can result in pregnancy complications.
Peripheral blood monocytes give rise to
M!s, tissue resident phagocytic cells whose
phenotype is specific to the tissue type.
These are involved in tissue homeostasis via
apoptotic cell clearance and the production
of important cytokines, chemokines, and
growth factors . They are foremost
prodigious phagocytic cells that clear more
than two 2X1011erythrocytes per day, recy-
cling iron as a necessary homeostatic
process . Moreover, M!s are the dedi-
cated janitors of the body, clearing cellular
debris from effete cells during tissue re-
modeling processes without eliciting an im-
mune response. Phagocytosis of cellular
components, along with varying environ-
mental cues, may lead to M! plasticity .
Such plasticity generates different types of
M!s possessing distinct phenotypes and
Emulating the Th1/Th2 nomenclature,
polarized M!s have been broadly catego-
rized as either pro-inflammatory (M1) or
anti-inflammatory (M2) . It is well es-
tablished that classically activated M1 M!s
are potent inducers of IL-1, TNF-, and IL-
12 following stimulation by a microbial anti-
gen or pro-inflammatory cytokines .
Originally described as M!s activated by
IL-4, alternatively activated M!s or M2
M!s have been described as anti-inflamma-
tory mediators [36,37]. Polarization of the
M2 phenotype can be induced not only with
IL-4, but also with immune complexes, IL-
10, glucocorticoid, or secosteroid hormones
. The M1/M2 paradigm has been com-
prehensively studied by transcriptional ap-
proaches, which defined skewed gene
expression based on the stimulus used to
generate each type of macrophage [34,39].
Recently, the M1/M2 paradigm has come
under scrutiny, as tissue resident M!s are
neither M1 nor M2 [11,40]. Thus, since M!s
are uniquely plastic cells, it has been pro-
posed to define M!s based on functions that
are involved in maintaining homeostasis,
such as host defense, wound healing, and
immune regulation .
Interestingly, M!plasticity plays impor-
tant roles not only in homeostasis and infec-
tion but also in cancer. As early as the late
1970s, it was found that tumor growth was
promoted by tumor-associated macrophages
(TAMs), a predominant leukocyte population
present in tumors with poor prognosis for
therapeutic outcome [41-43]. TAMs are dif-
ferent from Gr1+ myeloid-derived suppres-
sor cells (MDSCs) in mice, which are a
heterogeneous population of cells of the
myeloid lineage also associated with cancer
. However, because their defining marker,
Gr1, is only found in mice and has no homo-
logue in humans, the precise characterization
Houser: Decidual macrophages at the maternal-fetal interface
109Houser: Decidual macrophages at the maternal-fetal interface
Table 1. Macrophage Populations.
CD80/86, TNF-, IL-1,
SRA/B, MR, CD163,
CD23, IL-10, CXCR1,
Induced by TH1 or NK
cell production of IFN-
or other TLR-stimulated
APC TNF- production
Induced by TH2 or
Induced by TREG IL-10
production or IC,
Found in cancers, pro-
duce angiogenic and
tors including VEGF
population of myeloid
potent suppressors of
lipid metabolism, in-
and in tumors in
cellular debris and
effete cells during
and role of MDSCs in human infections and
cancer remains ill defined. TAMs, however,
have been found to aggregate in the hypoxic
regions of tumors, thereby promoting hy-
poxia-driven programs including angiogene-
sis, TNF- and TGF- production, and
CXCL8 secretion . Other chemokines in-
cluding CXCL1 and related molecules and
CCL2 have been associated with TAM accu-
mulation . Although TAMs have been
most closely associated to the M2 phenotype,
they are known drivers of chronic inflamma-
tory processes that promote epithelial hyper-
angiogenesis. Ultimately, this is followed by
dysplasia and invasive carcinoma . More-
over, their production of TNF- and IL-1
strongly indicates their regulation of cellular
TAMs, as well as M!s in general, also
have been shown to have a role in the con-
nection between sex steroids and inflamma-
tion in the promotion of cancer . One
study focused on gender disparities in hepa-
tocellular carcinoma, a cancer to which
males are more susceptible . This study
found that liver M!s in males produce
higher levels of IL-6 during carcinoma de-
velopment following induction via the hep-
atitis virus. Furthermore,
development was inhibited in males that
were IL-6 deficient. Interestingly, females
produce higher levels of estrogen steroid
hormones, which were found to inhibit IL-6
production in liver M!s and thereby protect
them from the development of cancer. This
study emphasizes the link between sex-
steroids, inflammation, and M! regulation
in the development of some cancers.
Hormones in tissue play important roles
in the development of tissue-resident M!s.
For example, glucocorticoids, which are re-
leased by adrenal cells in response to stress,
have been shown to inhibit M!-mediated
host defenses via the production of pro-in-
flammatory cytokines, leading to increased
susceptibility to pathogen infections .
However, other M! functions, such as
phagocytosis, are not impaired in the pres-
ence of glucocorticoids , suggesting that
glucocorticoids can directly impact tissue-
resident M! immune regulation. Proges-
terone, an important hormone during the
menstrual cycle and pregnancy, has been
shown to inhibit M! production of TNF-
in a pre-transcriptional manner  as well
as IL-12 induced nitric oxide (NO) produc-
tion in response to TLR4-mediated agonists
. Thus, it is conceivable that pregnancy-
specific hormones may directly contribute
to the rise and frequency of dM! popula-
tions and their responses to fetal-derived or
Environmental cues can lead to M!
plasticity and give rise to different popula-
tions of M!s that occur at various frequen-
cies. M!s at the maternal-fetal interface
experience a shift in hormonal production
both locally and systemically, encounter po-
tential pathogens, clear effete cells, and no-
tably interface and respond to non-self
invading trophoblast cells . The variety
of environmental cues during placental de-
velopment can lead to uniquely diverse, in
both phenotype and function, dM! popula-
tions in order to maximize different neces-
sary processes (Table 1). In fact, we have
now described two distinct dM! popula-
tions at the maternal-fetal interface .
DECIDUAL MACROPHAGES AS
ANTIGEN PRESENTING CELLS
The large abundance of M!s and near
absence of DCs  suggests that dM!s
may be the most important antigen process-
ing and presenting cells at the maternal-fetal
interface. dM!s, as a professional APC, may
be important in regulating both adaptive T
cell responses as well as innate NK cell re-
sponses at the maternal-fetal interface dur-
ing early human pregnancy.
M!s are equipped with a recognition
system for a host of different pathogen-as-
sociated molecular patterns (PAMPs) and
are specialized in the initial capture and pro-
cessing of these potential antigens. They are
also important in the development of an
adaptive immune response . Although
M!s are known for their powerful phago-
cytic and endocytotic capacities, antigen
presentation, by default, is left to the DC.
Houser: Decidual macrophages at the maternal-fetal interface
This may be in part because their high lev-
els of lysosomal proteases completely de-
grade engulfed antigens, a property not
shared with their DC counterparts [57-59].
It has now been shown, however, that
through M! activation, early phagosomes
actually have limited proteolysis and can ef-
fectively generate epitopes and present anti-
gens, while late phagolysosomes maintain
highly degradative capacity .
Tissue-resident APCs must be simulta-
neously capable of initiating a T cell re-
sponse to invading pathogens while
avoiding the risk of prematurely priming T
cells to seemingly innocuous events such as
apoptosis and cellular turnover. During
pregnancy, where the fetus is only partially
derived from its mother, this delicate bal-
ance is necessary for fetal survival. It is
known that the maternal adaptive immune
system can recognize paternal antigens, in-
cluding anecdotal evidence from women
who had multiple miscarriages but upon a
switch in partner they were successfully able
to carry a child to term . In addition,
mixed lymphocyte reactions have shown
that there is maternal immune cell suppres-
sion of fetal or paternal antigens during
pregnancy . Another study also demon-
strated that female mice can accept an allo-
geneic tumor of paternal origin during the
course of their pregnancy, but will reject the
same tumor if pregnant with a “third-party”
Although most studies emphasize the
role of suppression or regulation of T cell re-
sponses, very few have focused on the role
of the APC. An elegant study done in mice
demonstrated that DCs lose their ability to
migrate to draining lymph nodes following
decidualization and are consequently re-
tained within the uterus . Both mouse
and human endometrium are largely lacking
in lymphatic vessels; however, during
human decidualization, there is heightened
lymphangiogenesis that is not seen in mice
. This suggests that, in humans, if APCs
are capable of migrating to draining lymph
nodes, they could be equipped with potent
signals to alert effector T cells, emphasizing
the importance of a non-migratory APC,
such as the M! at the maternal-fetal inter-
We have now demonstrated that there
are two distinct subsets of dM!s found in
the early human placenta that can be sepa-
rated based upon CD11c expression and are
termed CD11cHIand CD11cLO. Interest-
ingly, CD11cHIdM!s were more efficient at
protein antigen processing and express
genes consistent with APC function, includ-
ing elevated levels of lipid-antigen present-
ing molecules such as CD1a, CD1c, and
CD1d compared to CD11cLOdM!s.
Although CD11c, a complement receptor,
is often exploited as a single marker to track
murine DCs, all human monocytes express
CD11c and may retain protein expression fol-
lowing tissue extravasation. Furthermore, ex-
pression is maintained during DC or M!
differentiation processes  and therefore
cannot be utilized in the same way to differen-
tiate between human DCs and M!s . The
similarities between murine CD11c+decidual
DCs and human CD11cHIdM!s are apparent
based upon antigen processing and presenta-
tion capacity ( and LG, BLH, JLS manu-
script in preparation). However, murine
CD11c+decidual DCs are capable of migrating
into the draining lymphnodes during preg-
nancy and are phenotypically distinct from
F4/80+M!s within the murine decidua tissue
. Moreover, both CD11cHIand CD11cLO
dM!s are phenotypically and functionally
macrophages and are equivalently capable of
phagocytosis . CD11cHIdM!s are found
in abundance compared to CD14-HLA-DR+
DCs , which comprise less than 1 percent
of the immune cell compartment at the mater-
nal-fetal interface . These differences in
abundance suggest that although there may be
overlapping functions, they are likely to be
performing specialized and distinct functions.
However, due to the low numbers of human
decidual DCs, experimentation, and therefore
a greater understanding of their function, is ex-
LIPID ANTIGEN PRESENTATION
Lipids are important for normal home-
ostasis, including wound healing, growth
111Houser: Decidual macrophages at the maternal-fetal interface
and hormone production. Blood lipid con-
centrations are elevated during pregnancy,
presumably for necessary fat storage and
fetal supply of fatty acids . They are also
important for the development of a variety
of hormones, which play integral roles dur-
ing pregnancy. It is therefore important that
phagocytic immune cells of the placenta are
capable of recognizing lipids derived from
cellular debris of effete decidual and tro-
phoblast cells versus lipids derived from
bacterial pathogens that threaten the health
of the mother and fetus.
Lipids are not water soluble and are
therefore always associated with membranes
or lipid-binding proteins, thus making the
immunogenicity of lipids different from that
of peptides. Lipids are transported through-
out the body in complex with apolipopro-
teins, internalized via the LDL receptor, and
delivered to the endocytic compartment,
where the lipid-protein complex is disman-
tled and distributed according to cellular
need . Other receptors, such as scav-
enger receptor A (SR-A), lectin-type oxi-
dized LDL receptor 1 (LOX1 or OLR1),
CD36, and other C-type lectins, can also
bind modified forms of LDL, including that
expressed by apoptotic cells . This sug-
gests several potential routes of entry for a
range of environmental lipid antigens.
Several lipid antigens that have been
characterized are either of bacterial or so-
matic origin. Generally lipid antigens are
found as either glycolipids or lipo-peptides
and are differentially distributed among en-
docytic compartments . Because differ-
ent types of lipids are sorted into different
endocytic compartments, it has been pro-
posed that CD1 trafficking evolved to sam-
ple the most appropriate lipid-containing
compartment . CD1 molecules are ge-
netically non-polymorphic cell-surface gly-
coproteins that present glycolipids and
lipo-peptides . CD1 genes have a simi-
lar intron/exon structure to MHC class I
genes and encode integral membrane pro-
teins consisting of three helices and an as-
sociated -2 microglobulin domain [74,75].
The 3 domain is the most similar between
all of the CD1 molecules, but is not com-
pletely homologous, to the MHC class I 3
domain . Loaded CD1 molecules that
reach the surface will be capable of present-
ing to T or invariant TCR NK (iNKT) cells.
TCRs recognizing group I CD1 loaded with
microbial antigens have highly diverse TCR
and chains, with a level of heterogeneity
similar to that of peptide-recognizing TCRs
Based upon protein sequence, CD1 iso-
forms can be classified into three groups:
group 1, which is comprised of CD1a,
CD1b, and CD1c; group 2, which is com-
prised of CD1d; and group 3, which is com-
prised of CD1e . Humans express all
CD1 isoforms, but these are generally re-
stricted to DCs and other professional APCs.
It has been shown that CD1a, expressed by
Langerhans cells, is able to efficiently pres-
ent antigens to CD1a-restricted T cells .
Dermal DCs and interdigitating DCs in
lymph nodes express CD1b [79,80]. CD1c
is largely expressed on B cell subsets, in-
cluding lymph node mantle zones and ger-
minal centers, in marginal zone B cells of
spleen and on a subpopulation of B cells in
adult and fetal peripheral blood [81-83].
Moreover, human CD1a, CD1b, CD1c,
and CD1d are all expressed by DCs, but ap-
pear at different stages of the monocyte-DC
differentiation process . Different ex-
pression patterns of CD1 on the cell surface,
early and late endosomal compartments,
lead to different rates of internalization into
endosomes , suggesting that each CD1
isoform may have a distinct role in the im-
mune response [73,86]. The different pat-
terns of CD1 expression are not completely
understood. In vitro studies using monocyte-
derived DCs have demonstrated that differ-
ing amounts of IgG in tissues can direct
CD1 expression profiles, an effect shown to
be mediated by FcRIIa on myeloid cells
. Also, Leslie and colleagues demon-
strated that lysophosphatidic acid and cardi-
olipin, lipids in normal human serum, are
modulators of CD1 expression via peroxi-
some proliferator-activated receptor (PPAR)
nuclear hormone receptors .
Placental lipids remain ill defined, and
their potential role in dM! expression of
112Houser: Decidual macrophages at the maternal-fetal interface
CD1 has yet to be characterized. However,
CD1 expression and lipid trafficking may
play currently unknown roles at the human
maternal-fetal interface. Recent observa-
tions from our lab found that CD1a and
CD1c molecules on the surface of CD11cHI
dM!s are functionally capable of presenta-
tion to clonal T cell lines (LG, BLH, and
JLS manuscript in preparation). These data,
along with the observation that there are
CD1 autoreactive decidual T cell clones,
lends further credence to the possibility that
placental lipids and CD1 presentation may
contribute to maternal-fetal immunotoler-
ance. These observations may help to better
understand lipids in pregnancy and in other
DECIDUAL MACROPHAGES AND
NK CELL CROSS TALK
NK cells were originally characterized
based on their innate cytolytic capacities,
which, unlike cytotoxic T cells, can directly
induce death of tumor cells or virus infected
cells . NK cells are also integral cy-
tokine producers in both physiological and
pathological conditions. Although NK cell
cytotoxic responses directly impact infected
cells, it is now thought that NK cell cytolytic
and cytokine responses can also regulate
antigen specific adaptive immunity via APC
priming and cross presentation .
NK cell function is based upon fine-
tuning of cell surface receptors that activate
or inhibit their responses . These recep-
tors signal through corresponding secondary
molecules that express immunoreceptor ty-
rosine activation motifs (ITAMs) or im-
munoreceptor tyrosine inhibitory motifs
(ITIMs). Each NK cell has a particular
repertoire of inhibitory and activating re-
ceptors on their surface . NK cell acti-
vation can be induced by overexpression of
activating ligands on cellular surfaces in the
absence/reduced expression of inhibitory
ligands. For example, NKG2D interacts
with several ligands that can be upregulated
in response to cellular duress, including
DNA damage responses, and induces NK
cell activation . Alternatively, NK cells
can respond to the absence of MHC class I
surface expression (“missing self”) .
MHC class I can be down-regulated by virus
infection or cellular transformation. NK
cells can become activated because in-
hibitory ligands such as CD94/NKG2A that
would normally recognize HLA-E or a vari-
ety of killer Ig-like receptors (KIRs) that
recognize HLA-A, B, and C on the cell sur-
face are missing, thereby tipping the balance
between inhibitory and activating receptors,
leading to NK cell activation [89,95]. These
results suggest that NK cells in steady-state
conditions with more inhibitory receptors
are poised for recognition of missing self
and therefore rapid clearance of MHC class
I deficient cells, whereas NK cells with
lower levels of inhibitory receptors are
poised for mobilization in response to
pathogen infections .
NK cells are the most abundant immune
cell type at the maternal-fetal interface .
Decidual NK cells are all CD56brightCD16-
and contain cytotoxic granules  but are
unique compared to CD56brightperipheral NK
cells . In an autologous setting, healthy
cells are spared from cytolysis due to a high
expression of self-MHC . However, at
the maternal-fetal interface, trophoblast cells
lack HLA-A and -B antigens, yet there is no
NK cell cytolysis. This may be in part due to
the fact that trophoblast cells express the
minimally polymorphic HLA-C and other
non-classical HLA molecules including
HLA-E, -F, and -G  that are recognized
by dNK cells. Although it is possible to en-
vision that dNK cells contact trophoblast
cells with an inhibitory synapse as opposed
to an activating synapse, it has now been
shown that dNK cells do in fact form an ac-
tivating synapse with MHC I null cells but
are unable to coordinate their microtubule or-
ganizing center (MTOC) with perforin-con-
taining cytotoxic granules, thereby disabling
them from killing their target . Com-
bined recognition of non-classical HLA mol-
ecules along with the inability to polarize
granules may spare fetal trophoblast cells
from dNK cell-mediated destruction.
The relatively large abundance of dNK
cells may be a potent source of cytokines and
113Houser: Decidual macrophages at the maternal-fetal interface
growth factors that are necessary for placen-
tal development. dNK cells are important
regulators of trophoblast invasion during ma-
ternal vasculature reconstruction . How-
ever, the induction of dNK cell activation as
well as regulation of NK cell responses has
yet to be characterized. One possible source
of dNK cell regulations is the dM! popula-
tion. dNK cells are in close proximity to
CD14+dM!s or DC-SIGN+dM!s , im-
plicating dM!s as potential mediators.
Alternatively, it was found that in mice
with MHC class I-negative tumors that
CD11c+DCs adoptively transferred pro-
moted NK cell-dependent anti-tumor effects
and that these effects were contact depend-
ent . These results suggest that APCs
can regulate NK cell function in vivo. Fur-
thermore, it has been shown that constant
cross-talk between NK cells and immature
DCs leads to DC maturation as well as an ini-
tial priming event in NK cells. This suggests
that continuous conversations between in-
nate immune cells can lead to enhanced in-
nate and adaptive immune responses .
Interestingly, CD1 molecules presented on
NK cell target lines that are HLA class I de-
ficient are capable of inhibiting NK cell cy-
tolytic responses [103,104]. Moreover, in the
same system, it was demonstrated specifi-
cally that targets expressing CD1b pulsed
with a known bacterial lipid antigen for
CD1b, enhanced NK cell inhibitory effects.
These results together suggest that
dM!s, or a specific population of dM!s that
are functionally close to DCs, might regulate
the large abundance of dNK cells at the ma-
ternal-fetal interface. Moreover, this particu-
lar interaction may occur by non-traditional
receptor-ligand interactions such as CD1
molecules. Thus, we propose that the innate
plasticity of M!s may allow for environmen-
tal signals to give rise to distinct dM! popu-
lations that play specific roles in regulating
both innate and adaptive immune responses
at the human maternal-fetal interface.
Human pregnancy and hemochorial
placentation challenges the conventional
view of the regulation of immune recogni-
tion of foreign antigens. The understanding
of how M!s, or populations of M!s, partic-
ipate in the maintenance of fetal-placental
tolerance could lead to a better understand-
ing of how the innate immune system regu-
lates both itself and the adaptive immune
system in order to induce tolerance to what
are non-self but non-pathogenic antigens.
By characterizing these findings, it is possi-
ble that the mechanisms discovered could be
exploited for the development of therapeu-
tics and/or therapeutic strategies to alleviate
human autoimmune and alloimmune dis-
Macrophage heterogeneity plays impor-
tant roles in the induction and cessation of in-
flammatory events, including those necessary
at the human maternal-fetal interface. We pro-
pose that two distinct dM! populations,
CD11cHIand CD11cLO, allow for integral
processes to be done in concert by specialized
CD11cHIdM!s are likely to be important for
the processing and presentation of lipid anti-
gen to decidual T cells through specific CD1
molecules (Figure 2). This is consistent with a
mechanism by which CD11cHIdM!s are ca-
pable of separating pathogenic and non-path-
ogenic lipids in order to amount to an
appropriate immune response at the maternal-
fetal interface without interfering with ongo-
ing tolerogenic mechanisms to fetal antigens.
It would be interesting to identify the lipid
components found at the human maternal-
fetal interface and their ability to dictate CD1
expression on dM!cell surface. Furthermore,
the lipids may vary in their ability to be loaded
into different CD1 molecules and their level
of antigenicity. Moreover, irrespective of lipid
processing and presentation, CD1 expression
by CD11cHIdM!s may be important in regu-
lating dNK cell cytokine responses and cellu-
lar expansion.This does not discount the fact
that dNK cells, as well as other cells, and
CD11cLOdM!s may also interact in alterna-
tive ways to regulate or respond to dNK cells.
However, CD11cLOdM!s may have more
phagocyte-specific function, which is impor-
tant for organogenesis and placental construc-
Houser: Decidual macrophages at the maternal-fetal interface
There are many aspects to understand-
ing how human dM! populations confer tol-
erance to fetal antigens. However, the key
may be in immune cell interaction and reg-
ulation with a particular emphasis on pla-
cental lipid diversity (or specificity) and
CD1 molecules. The distinct decidual
macrophage populations that we described
 may help to better understand how
macrophage heterogenity in pregnancy, and
in other tissues, plays specific roles. Fur-
thermore, the fact that only one population
of dM!s express CD1 molecules may indi-
cate important antigen presentation function
and lipid composition at the maternal-fetal
interface, an area that remains to be exten-
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