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For immunologists, ruminations about the immune sys-tem during pregnancy are mostly centred on the acqui-sition of maternal tolerance to the allogeneic fetus1,2.This view is probably too simplistic because it does nottake into consideration the anatomical fact that it is thematernal relationship with the placenta rather than withthe fetus that holds the key to our understanding of theimmunological paradox of pregnancy. In particular,the focus should be on the intermingling of placental andmaternal cells in the uterine wall, as this is where directtissue contact occurs during placentation. Failure to dis-tinguish between the local uterine immune response tothe placenta and the systemic immune response to fetalcells (which usually cross to the mother at delivery) hasled to a great deal of confusion.

To understand maternal uterine immune responsesto the placenta requires knowledge of the sequen-tial anatomical and physiological events that occurduring placentation. Herein lies a difficulty, in that

each species has developed its own strategy and thisresults in a great divergence of types of placentationin mammals35. One of the most obvious differencesis the extent of invasion into the uterus by placentaltrophoblast cells. This can range from no invasion at all(as in epitheliochorial placentation) to very extensiveinvasion (as in haemochorial placentation), wherebytrophoblast cellspenetrate through uterine blood ves-sels to come into direct contact with maternal blood.Humans have haemochorial placentae, as do manylaboratory animals, such as mice, rats, guinea pigs andrabbits, but even among this group, the human placentais particularly invasive.

Comparison of divergent placental strategies mustalso encompass the maternal reaction that each placentaltype evokes. Here there is also much diversity. In haemo-chorial placentation, the uterine mucosa is transformedinto a highly specialized tissue known as the decidua(a process referred to as decidualization). This doesnot occur in species with non-invasive epitheliochorialplacentae. In primates, decidualization correlates closelywith the degree of invasion, so the most marked decidualchange is seen in those species with the most invasiveplacentae. A conspicuous feature of the decidua is theinflux of a distinctive lymphocyte population of maternaluterine natural killer (NK) cells6. NK cells are emergingas important players in the uterine immune response toinvasive forms of placentation, although the precise rolethey have is still unclear.

The cells that define the boundary between themother and fetus are trophoblast cells7. These cells arederived from the outer layer of the blastocyst and have

many unusual characteristics that tend to be ignoredby immunologists8(BOX 1). Because trophoblast cells arefreed from the developmental constraints that affect therest of the embryo, they have a unique pattern of pater-nal and maternal gene expression. Of most relevance toimmunologists is the expression of MHC and MHC-likegenes by trophoblast cells, which would be the poten-tial ligands for immune receptors on uterine NK cells,lymphocytes and myelomonocytic cells. Human tropho-blast cells have been studied extensively and express aunique and intriguing array of HLA class I molecules, thefunctions of which might hold the key to the successfultemporary coexistence of two individuals.

Kings College, Cambridge

CB2 1ST, UK.

Correspondence to A.M.

e-mail: [email protected]

doi:10.1038/nri1897

Trophoblast cells

Trophoblast cells are the

earliest extra-embryonic cells

to differentiate from the cells of

the mammalian embryo. They

surround the conceptus

throughout gestation and arein direct contact with maternal

tissues.

Blastocyst

After fertilization, the potential

embryo undergoes mitotic

division and, at the 128-cell

stage in humans, two distinct

cell lineages are present.

Trophoblast cells are derived

from the trophectoderm that

surrounds the blastocyst and

the inner cell mass gives rise

to the embryo.

Immunology of placentationin eutherian mammals

Ashley Moffett and Charlie Loke

Abstract |The traditional way to study the immunology of pregnancy follows the

classical transplantation model, which views the fetus as an allograft. A more recent

approach, which is the subject of this Review, focuses on the unique, local uterine

immune response to the implanting placenta. This approach requires knowledge of

placental structure and its variations in different species, as this greatly affects the typeof immune response that is generated by the mother. At the implantation site, cells from

the mother and the fetus intermingle during pregnancy. Unravelling what happens here

is crucial to our understanding of why some human pregnancies are successful whereas

others are not.

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Eutherian placenta

Eutherian mammals include all

mammalian species except

marsupials and egg-laying

monotremes. The eutherian

placenta is well developed

compared with the marsupial

placenta and has a great

diversity of forms.

Amniote egg

Eggs of amniote vertebrates

provide an interface between

the embryo and its immediate

environment, therefore

allowing increased respiratory

and excretory capacity as well

as nutrient provision.

Yolk sac

The first of the four extra-

embryonic membranes of

amniote eggs to form during

embryogenesis. It surrounds

the mass of yolk in reptile and

bird eggs and is connected to

the midgut by the yolk stalk.

The yolk sac is also formed in

mammals, despite the absence

of yolk.

Amnion

The innermost membranous

sac of amniote eggs. It is filled

with a serous fluid and

encloses the embryo of an

amniote (reptile, bird or

mammal).

It is therefore clear that a detailed knowledge of theanatomical and molecular interactions between the pla-centa and the uterus at the implantation site is necessaryif we are to understand natures allograft. The startingpoint of this Review will be the eutherian placenta. Theevolution from the extra-embryonic membranes ofamniote eggs to the formation of the definitive placentais traced and the diverse characteristics of placentae thatare seen in extant mammalian species is emphasized.The unique characteristics of trophoblast cells and theadaptation of the uterine mucosa by transformation intodecidua are described. Also, the immunological implica-tions of these divergent placental forms are considered.It is hoped that this approach will provide a more solidframework on which to discuss the immunology of mam-malian reproduction, especially from the standpoint ofthe success or failure of human pregnancy.

Evolution of viviparity

Viviparity(the bearing of live young)has evolved inde-pendently many times in many groups of vertebrates,

including fish, reptiles and mammals911. The selectivepressures for viviparity include protection of offspringfrom cold, from inhospitable environments and frompredators. The spectrum of viviparity seen today rangesfrom a mother simply holding yolky eggs in her body untilthey hatch (ovoviviparity) to the development of a complexplacenta that extracts nutrients from the mother.

The placenta is formed when fetal membranes becomeclosely attached to the uterine wall to facilitate physiologi-cal exchange of gases, nutrients and waste products. Thefirst step in the emergence of placentation was the evolu-tion of the amniote egg, which was an important verte-brate innovation10,11. This paved the way for the transitionfrom oviparity to viviparity and a shift from yolk-sacnutrition to nourishment delivered by the mother 4,12. The

crucial modification from the anamniote to amniote eggis the development of four extra-embryonic membranes,consisting of the yolk sac, amnion, chorionandallantois. Theegg shell was subsequently lost during the evolution of

viviparous animals, but all amniote embryos retain theseextra-embryonic membranes. Only minor modificationswere then required for the evolution of these into thedefinitive placenta.

Mammals can be divided into three subclassesthat became separated from the reptile-like mammals120 million years ago, and these are known as themonotremes (for example, duckbill platypus), marsupi-als (for example, kangaroos) and eutherians (for exam-ple, humans). Monotremes are oviparous and the egg isretained in the oviduct until shortly before the younghatches. The eggs of marsupials hatch in the oviduct atthe 10-somite stage of development, when the embryoimplants briefly and superficially with a simple placenta.The eutherians have the most complex placental develop-ment. The main evolutionary change in mammalianplacental development was the emergence of trophoblast

cells as a distinctive cell type from the outer epithelium(chorion) of the amniote egg.

Anatomy of placentation in eutherian mammals

Bringing order to the seeming chaos of placentaldiversity is difficult, but for immunologists the mostimportant consideration is the invasive potential oftrophoblast cells in each species and how this is regu-lated. Traditionally, the various complex types of placen-tation seen in eutherian mammals have been viewed asthree simplified groups, based on the number of inter-

vening cellular layers between the maternal and fetalcirculations 13(FIG. 1). Trophoblast cells are always theoutermost layer of fetal cells that overlie an inner coreof mesenchyme and fetal capillaries. In epitheliochorialplacentation, the trophoblast cells can attach (and evenfuse with) the surface epithelium of the uterus but thereis no invasion by the trophoblast cells. Trophoblast-cellinfiltration through the surface epithelium of the uterusis characteristic of other placental forms. For example,trophoblast cells can migrate to abut maternal blood

vessels (in endotheliochorial placentation). The mostinvasive form is seen when trophoblast cells infiltratethrough the maternal vessels to come into direct contactwith maternal blood (in haemochorial placentation). Inthis haemochorial form, trophoblast cells disrupt theendothelial cells and, in some cases, the muscle coat

(media) of the uterine arteries as well.Molecular phylogenetics has allowed placental struc-

ture to be viewed in a new context, although some ques-tions still remain14. All extant eutherian mammals canbe grouped into four superorders (or clades): Afrotheria,Xenarthra, Laurasiatheria and Euarchontoglires (orSupraprimates)15. Although the relationship between theclades is still disputed, by studying retroposed elements,the basic eutherian divergencewas found to be betweenXenarthra and the other clades16. All placentae examinedso far from eutherian mammals of the Xenarthra clade(such as armadillos and sloths) are either haemochorial orendotheliochorial, whereas non-invasive epitheliochorial

Box 1 | Characteristics and functions of trophoblast cells

Characteristics

Paternal X chromosome inactivation

Unmethylated DNA

Expression of endogenous retroviral products (such as syncytin)

Expression of oncofetal proteins (such as carcinoembryonic antigen, -fetoproteinand human placental lactogen)

Formation of multinucleated cells by fusion or endoreduplication

Lack of expression of MHC class II antigens and variable expression of MHC class I

antigens

Functions

Anchoring the placenta to the uterine wall

Transport of nutrients and oxygen to the fetus

Removal of waste products

Secretion of hormones and other placental proteins

Physical barrier between maternal and fetal circulations

Site of contact between the maternal immune system and the conceptus

Transfer of maternal immunoglobulins to the fetus*

Phagocytosis of red blood cells for acquisition of iron*

*Species-specific functions. For more details, see REFS 8,85.

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Uterineepithelium

Maternaluterine vessel

Fetal vessel

Trophoblast cell

Fetal vessel

Cytotrophoblast cell

Fetal vessel

Syncytiotrophoblastlayer

Maternal bloodin intervillousspace

a Epitheliochorial b Endotheliochorial c Haemochorial

Maternaluterine vessel

Trophoblast cellFetalmesenchyme

Maternaluterine vessel Endometrium

Chorion

In birds and reptiles, the

chorion adheres to the shell

and is highly vascularized to

function in gas exchange. In

mammals, it forms the fetal

contribution to the placenta,

made by an outer layer of

trophoblast cells and inner

layer of extra-embryonic

mesoderm, which contains

blood vessels that allow

exchange of materials with the

maternal circulation.

Allantois

The extra-embryonic

membrane that emerges as a

sac from the posterior part of

hindgut of the embryo. It fuses

with the chorion to form the

chorio-allantoic placenta. The

connection it makes between

the embryo and the placenta

becomes the umbilical cord.

Retroposed elements

Retroposons randomly insert

into the genomes with little

likelihood of the same element

integrating into the

orthologous position in

different species. Analysis of

the patterns of presence or

absence of retroposons is a

reliable method for studying

the evolutionary history of

organisms.

Convergent evolution

The process wherebyorganisms that are not closely

related independently acquire

similar characteristics while

evolving in separate and

sometimes varying

ecosystems.

Haemolytic disease of

the newborn

If there is rhesus-blood-group

incompatibility between the

mother and her fetus,

the mother makes an antibody

response against fetal red

blood cells that access the

mothers circulation at delivery.

These IgG antibodies cross the

placenta during a subsequent

pregnancy, which results in the

destruction of fetal red blood

cells, leading to haemolytic

disease of the new born.

Maternal and fetal

microchimerism

The presence of fetal cells in

the mother or maternal cells

in the fetus. Fetal or maternal

cells generally cross the

placenta at delivery and might

persist for many years.

placentation (as is found in marsupials) is not seen17,18. Itis still uncertain what the primordial form of eutherianplacentation is and there are compelling arguments thatthis was the endotheliochorial form14,17. However, a recentphylogenetic analysis combined with morphological andmolecular data indicates that the ancestral placenta washaemochorial and invasive19.

The observation that haemochorial placentae arefound in diverse species belonging to all four eutheriansuperorders is consistent with convergent evolution andthe presence of strong selective pressures that favourthis condition, presumably to provide the fetus with easyaccess to nutrients directly from the maternal blood.However, the disadvantage of this form of placentationis that the mother and fetus are no longer separated byan intact layer of epithelial cells and this allows exposureof the trophoblast cells to potential allogeneic immuneresponses by the mother. Uterine immune responsesmust therefore allow the placenta access to maternalsupplies but at the same time prevent excessive invasion.In addition, the transfer of cells between the mother andthe fetus becomes more likely in haemochorial placen-tation. In humans, fetal cells invariably cross into the

maternal circulation at birth and a maternal antibodyresponse to incompatible red blood cell antigens such asRhesuscan result in haemolytic disease of the newborn insubsequent pregnancies20.A long-term consequence ofthis cellular deportation is microchimerism, in which fetalcells persist in the mother for several decades. The pres-ence of increased numbers of fetal cells is associated withdiseases such as systemic sclerosis, giving rise to the ideathat such diseases might have an alloimmune rather thanautoimmune pathogenesis21. Haemochorial placentationcan be viewed as a trade-off between the risk of theseadverse immunological reactions and the need for anefficient way of obtaining nutrients from the mother.

Maternal uterine response to placentation

Concomitant with the marked degree of placentaldiversity in different species, there is also variationin the uterine response to placentation that correlatesclosely with the extent of trophoblast-cell invasion.In epitheliochorial placentation, there are minimalchanges in the stroma of the uterine mucosa duringpregnancy, apart from local angiogenesis, which isneeded to increase the blood flow and deliver nutri-ents to the uterine surface. By contrast, haemochorialplacentation is characterized by two changes in theuterus, the differentiation of the endometrium intodecidua and the transformation of the uterine spiralarteries. In the two extremes of placental types, thenon-invasive epitheliochorial form and the invasivehaemochorial form, it is obvious that the mechanismsfor increasing the blood flow to the fetoplacentalunit are completely different. In epitheliochorialplacentation, this is achieved by expansion of the sizeof the vascular bed in the uterus by angiogenesis. Bycontrast, in human haemochorial placentation, thereis lowering of resistance in the vessels of the placentalbed caused by modification of the walls of pre-existing

arteries, resulting in increased low-pressure bloodflow22,23(FIG. 2).

The changes of decidualization involve all the cel-lular elements of the uterine mucosa and are mostpronounced in humans. The most obvious featuresare enlargement of the uterine stromal cells and thepresence of a distinct lymphocyte population of uter-ine NK cells6(BOX 2). In all species, the hallmark ofthe decidua might indeed be the presence of uterineNK cells. Similar cells are not found in other tissues,and whenever decidual tissue is formed uterine NKcells are present (even in ectopic locations such as inendometriotic foci)24.

Figure 1 | Types of placentation. Schematic representation of the three main types of placentation, showing the

relationship between the fetal trophoblast cells and maternal blood. a | Epitheliochorial. Trophoblast cells of the placenta

are in direct apposition with the surface epithelial cells of the uterus but there is no trophoblast-cell invasion beyond this

layer. b | Endotheliochorial. The uterine epithelium is breached and trophoblast cells are in direct contact with endothelial

cells of maternal uterine blood vessels. c | Haemochorial.Maternal uterine blood vessels are infiltrated by trophoblast cells

causing rupture and release of blood into the intervillous space. The outer layer of the chorionic villi (syncytiotrophoblast)is now bathed in blood like a mop in a bucket of blood.

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Amniotic cavityMyometrium

Placenta vascularizedby allantoic vessels

Cervicalcanal

Uterine artery

Arcuate artery

Allantoic vesselsin umbilical cord

Arcuate artery

Radial artery

Arcuate artery

Radial artery

FetusNormal pregnancy Pre-eclampsia and fetal growth restrictionc

Spiral arterialwall replacedby trophoblastcells(endovascular)

Basalartery

Myometrium

Deciduabasalis

Placenta Placenta

AmnionChorion

Decidua parietalis

Remnantsof yolk sac

Decidua basalis

Radial artery

a

b

Villoustrophoblastcell

Maternalblood in

intervillousspace

Extravilloustrophoblastcells(interstitial)

Placentalbed giantcells

Placental villoustree has fewerbranchesbecauseof alteredblood flowcharacteristics

Spiral arteryremainsnarrowedin this segment

Deciduabasalis

Media Media

Endothelium Endothelium

Systemic sclerosis

A chronic autoimmune disease

that causes a hardening of the

skin. The skin thickens because

of increased deposits of

collagen. Compared with the

localized form of the disease

(scleroderma), systemic

sclerosis causes more

widespread skin changes and

can be associated with damage

to the lungs, heart and kidneys.

Endometriotic foci

Foci of endometrial tissue

outside the endometrium or

myometrium (muscle wall) of

the uterus. They are usually

found in the peritoneum.

Reproductive failure in humans

In humans, it is clear that disruption of the normal balancebetween the itinerant trophoblast cells and the uterine tis-sues they colonize during placentation can result in vari-ous clinical problems. These conditions give insight intohow the delineation of the territorial boundary between

two individuals is achieved. Because of the close corre-lation between the invasion of trophoblast cells and theextent of decidualization, it was argued that the decidualtissue has a permissive influence that favours trophoblast-cell invasion into the uterus25. The alternative view wasthat the decidua provides a defensive riposte to the highly

Figure 2 | Disorders of human pregnancy resulting from abnormal placentation. a | The blood supply to the human

pregnant uterus is shown. b |Normal pregnancy.The spiral arteries of the placental bed are converted to uteroplacental

arteries by the action of migratory extravillous trophoblast cells. Both the arterial media and the endothelium are

disrupted by trophoblast cells, converting the artery into a wide calibre vessel that can deliver blood to the intervillous

space at low pressure. The small basal arteries are not involved and remain as nutritive vessels to the inner myometrium

and decidua basalis.c |Pre-eclampsia and fetal growth restriction.When trophoblast-cell invasion is inadequate, there isdeficient transformation of the spiral arteries. The disturbed pattern of blood flow leads to reduced growth of the

branches of the placental villous tree, which results in poor fetal growth.

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Tubal pregnancy

An ectopic pregnancy occurs

when the blastocyst implants

at a site outside the uterus.

Most ectopic pregnanciesoccur in the fallopian tube so

the terms ectopic pregnancy

and tubal pregnancy are nearly

synonymous.

Placenta creta

A condition when placental

trophoblast cells invade deeply

into the muscle coat

(myometrium) of the uterus,

usually because of the absence

of decidua. This can lead to

uterine rupture, torrential

haemorrhage and failure of the

placenta to separate after

delivery.

Procrustean bed

In Greek mythology, Procrustes

(whose name means he

who stretches) was a host who

adjusted his guests to their

bed. If they were longer than

the bed, he cut off the

redundant part; if shorter, he

stretched them till they fitted

it. Any attempt to reduce men

to one standard, one way of

thinking or one way of acting,

is called placing them on a

Procrustean bed.

invasive trophoblast cells26. Mothers compromise, and itnow seems probable that both ideas are correct and thatthe decidua allows orderly access of trophoblast cellsto the maternal nutrient supply by achieving the rightbalance between under- and over-invasion.

Trophoblast-cell penetration of the uterine epithe-lium and invasion into the uterine wall and arteries ispotentially highly dangerous, particularly in humans.Uncontrolled trophoblast-cell invasion is seen whenthe decidua is deficient or absent, as in tubal pregnancyor when the placenta implants on scar tissue froma previous Caesarian section, a condition known asplacenta creta27. Without medical intervention, theseconditions result in maternal death from haemorrhage.Early studies in which trophoblast cells were trans-planted to ectopic sites in mice and pigs showed theinherent invasive proclivities of trophoblast cells26. Thedecidua can be considered to behave as a Procrustean

bed, violently forcing conformity on its guests what-ever their shape or size a harsher view of maternalcompromise28.

At the opposite extreme, excessive restraint of tro-phoblast cells by the decidua can result in pregnanciesin which trophoblast-cell invasion into the arteriesand uterine wall is inadequate. In this case, the territo-rial boundary has moved in favour of the mother andthe blood supply to the fetus becomes poor. The mainproblems that result from such reduced blood supplyare fetal prematurity, fetal growth restriction, still-birthand pre-eclampsia, and in many of these pregnanciesthe main defect is reduced trophoblast-cell infiltration

into the uterus22(FIG. 2c). The extent to which all of theseconditions occur in apes and monkeys is difficult toascertain, but pre-eclampsia seems to be restricted tohumans. Pre-eclampsia has a high maternal and fetalmortality rate and mainly affects first-time mothers.Why should such a devastating disease be maintaineddespite the strong selective pressures for reproductivesuccess? The answer probably lies in the delicate nego-tiation between trophoblast-cell invasion and deciduathat is required during every human pregnancy. The fewmothers dying from pre-eclampsia can be viewed as anevolutionary consequence, or indeed sacrifice, becauseof the need to control the aggressive behaviour of humantrophoblast cells.

Placentation in primates

Interestingly, not all primates have haemochorial pla-centaebut they are seen in all higher primates such asmonkeys, apes and humans, although the pattern oftrophoblast-cell invasion differs29(FIG. 3a). In particular,interstitial invasion into the decidual stroma and myo-

metrium is a prominent feature in humans, whereas onlyvascular migration has been seen in Rhesus monkeys30.The pattern of trophoblast-cell infiltration in the greatapes is not known. Humans clearly have evolved auniquely invasive form of placentation that is potentiallydangerous to the mother. So, what selective pressuresmight be driving these changes? The most obvious dif-ferences between humans and apes are bipedalism andenlarged brain size. Both these characteristics couldinfluence reproductive strategies.

The physiological responses that are necessaryto redistribute blood flow to the uterus are likely toalter with bipedalism31. The cardiac output is affectedbecause of compression of the inferior vena cava by thelarger uterus and also by the increased sympathetictone (that is, increased peripheral vascular resistanceand heart rate) required to ensure perfusion of bloodto the brain against the pull of gravity. These conse-quences of bipedalism might place selective pressures toincrease structural transformation of the uterine arter-ies by trophoblast cells to ensure that the uteroplacentalblood flow that is required for fetal development can beachieved throughout pregnancy.

In the third trimester of human pregnancies, to sup-port development of a large brain, 60% of total nutri-tional needs are directed to the fetal brain comparedwith only20% in other mammalian pregnancies32.

However, large brains are not limited to species withhaemochorial placentation, as dolphins (which haveepitheliochorial placentae) have the second largest brainafter humans. Evolution of the large human brain, at atime when the form of haemochorial placenta in higherprimates was already in place, required modifications ofthe primate haemochorial placenta to allow increaseddelivery of oxygen and nutrients through the uterinearteries. To achieve this, trophoblast cells might have toinvade deeper into the uterine wall to modify the struc-ture of the uterine arteries so that they are converted tothe high-conductance vessels that are required for thedevelopment of our large brains.

Box 2 | Characteristics and functions of human uterine NK cells

CD56hiCD16 uterine natural killer (NK) cells are similar to the minor CD56hiCD16

NK-cell population in the blood but with phenotypic differences from both CD56low

and CD56hi blood NK-cell subsets.

They represent 70% of leukocytes at the implantation site.

They might arise ab initio from a separate lymphoid lineage or differentiate in the

endometrial microenvironment from blood CD56hi NK cells.

They produce a range of soluble products, including angiogenic cytokines (such as

angiopoietin-2and vascular endothelial growth factor C88) and lytic enzymes (such as

granzymes and perforin).

The diagnostic tests used to evaluate NK-cell phenotype and activity in the peripheral

blood of women with reproductive failure give no information regarding uterine

NK-cell function89.

Therapeutic regimes to downregulate NK-cell activities or numbers (including

steroids or intravenous immunoglobulins) to treat pregnancy failure have little

scientific basis89.

Similar cells are found in species with haemochorial placentation. These have been

called granulated metrial gland cellsin rodents or Kurloff cells in guinea-pigs9092.

In all species, they are always associated with the spiral arteries that supply the

placenta but their spatial association with trophoblast cells is more variable.

Their functions are unknown, but possible roles include: first, to maintain themucosa and stability of blood vessels (in the non-pregnant endometrium). NK cells

are only found in the non-pregnant endometrium in menstruating primates when

there is an associated pronounced decidual reaction93. Second, to modify the walls

of spiral arteries (in the decidua). Third, to control trophoblast-cell invasion of the

decidua, myometrium and arteries (at the implantation site).

For more details, see REFS 6,86,87.

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Placenta

Fetal vessel

Cord and fetus

Central arterialcanal lined by

trophoblast cells

Mesometrium

Junctional zone

with glycogen cells

Uterine artery

Spongiotrophoblastcell

Maternal bloodspace

Myometrium

Decidua basalis

Mesometrial trianglecontaining NK cells

Labyrinth

area

Endothelium

Media

Radial artery Radial artery Radial artery

Decidua

Myometrium

Placenta

Maternalblood

Fetal vessel

Trophoblast-cellshell

Cord and fetus

Trophoblast cellsinfiltrate theendotheliumand mediaof spiral arteriesto replace the wall

Intervillous space

Placental villoustree coveredby villoussyncytiotrophoblast

b Implantation site of mouse at day 13 of pregnancya Implantation site of rhesus monkey

Pre-eclampsia

Eclampsia (in Greek meaning

bolt from the blue) describes

grand mal seizures (epileptic

fits) occurring towards the end

of pregnancy. Pre-eclampsia

describes the symptoms that

precede eclampsia, which

include oedema, proteinuria

and hypertension.

Inferior vena cava

The large vein that carries

de-oxygenated blood from

the lower half of the body

to the heart.

Placentauterine immune interaction

So, what does placental development have to do with theimmunology of reproduction? The standard approachof immunology text books is to view the fetus as anallograft, a situation that can be associated with strongantibody and T-cell-mediated responses to the allogeneicMHC molecules expressed by the vascularized graft. This

approach does not distinguish between fetal cells in thecirculation or trophoblast cells in the uterus nor does itencompass the different placental forms. For example, inhaemochorial placentation, although the decidua avoidsclassic allogeneic rejection of trophoblast cells, the depthof trophoblast-cell invasion is regulated. To understandthe mechanisms involved, both the anatomy of placenta-tion and the maternal leukocytes present in the lining ofthe uterus are clearly important considerations. In addi-tion, it is crucial that the MHC status of trophoblast cellsis considered, as these molecules can function as ligandsfor uterine immune cells, including T cells, NK cells andmyelomonocytic cells. Trophoblast-cell populations are

always negative for MHC class II expression, indicatingthat they cannot present antigen directly to maternalCD4+ T cells. The most definitive data on MHC expres-sion are for the human placenta, whereas the picture inother species is limited and confusing. Obviously, thesespecies differences in placentation and MHC expressionmean that humans and other primates need to be consid-

ered separately from species using other placental strat-egies (particularly those without decidua), as the localuterine immune responses are likely to be dissimilar.

Immune responses in epitheliochorial placentation.Inmost cases of epitheliochorial placentation, the allan-tochorion trophoblast cells that contact the uterineepithelium lack expression of both MHC class I and IImolecules. There are however species-specific excep-tions, with MHC-class-I-expressing trophoblast cellsdescribed at certain sites and stages of gestation inseveral species. For example, in horses, MHC-class-I-positive trophoblast cells do invade into the uterus to form

Figure 3 | Placentation in rhesus monkeys and mice. a | In contrast to humans, the structural and destructive changes

to the uterine vessels of Rhesus monkeys are not so marked (FIG. 2). The arteries are only invaded in an endovascular

manner, with trophoblast cells migrating down the lumen of the blood vessels and replacing the endothelium and

eventually the media94. Interstitial trophoblast-cell invasion and the decidual reaction is very limited and no invasion of the

myometrium occurs. Instead, there is a well-developed trophoblast-cell shell that forms a clear demarcation line between

the placenta and uterine tissues. A similar pattern is found in baboons95. b | In mice, the area of placental exchange ofnutrients is the labyrinth, which is provided by extensive branching of the chorionic villi and is analogous to the villous

placenta in humans. Natural killer (NK) cells are abundant in the decidua basalis on days 810 of pregnancy. By day 13 of

pregnancy, there are very few NK cells remaining in the decidua basalis and they are found in the mesometrial triangle, an

area formed by the two layers of the myometrium.

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Endometrial cups

A focal collection of

trophoblast cells that

penetrate the uterus of horses.

These cells are responsible for

secretion of equine chorionic

gonadotrophin.

Ectoplacental cone

A core of rapidly dividing

trophoblast cells with an outer

layer of giant cells that is

present in the developing

mouse conceptus at 7.5 days

post-coitum.

transient endometrial cups that are surrounded and even-tually destroyed by maternal lymphocytes. In addition,maternal antibody responses to paternal MHC class Iantigens are often generated in horses, but cytotoxicT-cell responses against paternal alloantigens are reducedcompared with such responses before pregnancy, indi-cating an asymmetric immune response to the fetus33.Subpopulations of bovine trophoblast cells seem toexpress mRNAs that are encoded by both classical andnon-classical MHC class I genes34. In sheep, binucleatetrophoblast cells fuse with the epithelial cells that line theuterus, creating a condition known as synepitheliochorialplacentation. Although the binucleate cells express MHCclass I molecules35, the potential immunological effects ofthis fusion between two allogeneic cells are not known.

In species that use epitheliochorial placentae, thesimple apposition between the placenta and uterineepithelium might not provoke any damaging immuneresponses by the mother. The conceptus in these speciescould be regarded as similar to commensal bacteria inthe gut, generating minimal immune recognition by thehost unless they breach the epithelial-cell barrier. In otherwords, the conceptus is non-self, settled innocuously inan epithelial-cell-lined lumen. Although intraepithelialgranulated lymphocytes, which are characteristic ofmucosal surfaces, have been described, the endometrial

stroma in epitheliochorial placentation lacks NK cells36.This indicates that a different immune response to theplacenta occurs in species that use epitheliochorial pla-centae than in those species that have trophoblast-cellinvasion and decidualization.

Immunology of rodent placentation.Haemochorial pla-centation is a feature of most rodents (FIG. 3b) but it differsfrom that in humans with regard to the depth of inva-sion by trophoblast cells and the pattern of distributionof uterine NK cells around the spiral arteries that supplythe placenta3740 (TABLE 1). Even among rodents, there aresignificant variations. In mice, the presence of uterine NK

cells in the media of the arteries indicates that they mighthave a direct physiological role in regulating the bloodpressure and flow to the placenta. In support of this, preg-nant mice with no uterine NK cells retain the vasculararchitecture that is typical of the non-pregnant state41.Mouse uterine NK cells might also indirectly modify theblood flow through an effect on trophoblast-cell behav-iour (as seems to be the case in humans), because directcontact occurs between uterine NK cells and trophoblastcells when the ectoplacental cone moves into the decidualtissue on day 8 of gestation. The receptors expressed byuterine NK cells might give insights into how these cellsfunction, but information on the expression by uterineNK cells of members of the Ly49 family (which carry outthe same function as killer-cell immunoglobulin-likereceptors (KIRs) in primates) and about their cognateligands on trophoblast cells is sparse. It is therefore notclear whether uterine NK cells have the same role or usethe same molecular mechanisms in mice and humans.

T-cell recognition of paternal alloantigens expressed bythe fetus was shown to occur in mice in which all T cellsexpressed a transgenic T-cell receptor specific for pater-nal alloantigens, and this resulted in transient toleranceof the transgenic T cells42. But where in the feto-placentalunit are these alloantigens expressed? The most glaringomission that has so far prevented a clear understanding

of mouse reproductive immunology is the lack of defini-tive information on the MHC expression status of mousetrophoblast cells. It seems that the labyrinthine trophoblastcells are MHC class I and class II negative. By contrast, thespongiotrophoblast cells that separate the labyrinth layerfrom the decidua have been shown to express polymor-phic paternally derived MHC class I molecules43,44. It is notknown which MHC class I loci encode these products norwhether any non-classical MHC molecules are present45.

Disruption of many immunological pathways canlead to reproductive failure in mouse models, but cau-tion is needed in interpreting the results because it isoften unclear whether the failure is caused by a classical

Table 1 | Differences between mouse and human placentation

Characteristics Mouse Human

Intravascular trophoblast-cell invasion

Minimal* Extensive

Arterial transformation Largely independent of trophoblastcells

Caused by perivascular and endovasculartrophoblast cells

Decidua Formed after implantation only at site ofplacentation Formed in late-secretory non-pregnantendometrium, involving entire uterine mucosa

NK cells Infiltrate the media of arteries anddisrupt vascular architecture

Encircle adventitia of arteries. Probably havesome direct effect on arterial function but mainlyact through indirect effects on trophoblast-cellinvasion

NK-cell receptors KIR genes not functional. The Ly49family fulfils the same function ashuman KIRs, but Ly49 expression byuterine NK cells and MHC expression bytrophoblast cells are unknown

Highly diverse KIR genes. The KIR ligands HLA-Gand HLA-C are present on migratory trophoblastcells

*In guinea-pigs91, trophoblast cells migrate through the media out of the uterus into the mesometrial artery. This species has a longgestation period. Hamsters90 have prominent granulated lymphocytes that form a sheath around the arteries. In rats, in late gestation39,trophoblast cells extend as far as the mesometrial triangle. KIR, killer-cell immunoglobulin-like receptor; NK, natural killer.

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Syncytiotrophoblast

The outermost trophoblast-cell

layer covering the chorionic villi

that is formed by fusion of the

underlying layer of

mononuclear trophoblast cells

to become a multinucleated

syncytium, which forms a

barrier between the fetus and

the mother.

allogeneic response or due to some other immunologicalmechanism such as inflammation.Paradoxically, the nor-mal controls used in many of these models are syngeneicpregnancies, clearly something of an oxymoron whenthinking of normal human pregnancy4648.Furthermore,in another classic mouse model of abortion CBA/Jmice (H2k) crossed with DBA/2 mice (H2d) the nor-mal control mating is with a BALB/c male (which is alsoH2d), so it is not certain whether the fetal losses in CBA/J DBA/2 matings have an alloimmune basis owing toMHC differences4951. In another model, T-cell reactivityto the conceptus could be implicated because ligationof the T-cell-expressed co-stimulatory molecule CD40ligand led to pregnancy loss47. However, the mechanismof pregnancy failure proved to be caused by dysfunc-tional ovaries (ovarian insufficiency) resulting fromexcessive inflammation in the ovary. Despite thesecaveats, lessons can be learnt.

When syngeneic matings are used, analysis of gene-knockout animals has indicated that pregnancy failure(resorption) results from the lack of genes that seem to

have functions that prevent excessive inflammation atthe implantation site52,53. These genes encode proteinssuch as the complement regulator Crry (complement-receptor-related protein) and CD95 ligand (CD95L, alsoknown as FASL)52,53. Other models using allogeneic mat-ings have helped to explain how adverse T-cell responsesmight be avoided; for example, by mechanisms involvingindoleamine 2,3-dioxygenase (IDO), T-cell co-stimulatorymolecules (such as CD80, CD86 and programmed deathligand 1 (PDL1)) and immune deviation to T helper 2(T

H2)-type responses46,50,51,54,55. There is presumably

redundancy in the system, because mice deficient in IDOor T

H2-type cytokines reproduce normally56,57. Notably,

many of these pathways might affect the generation ofregulatory T cells, which are known to be increased inmouse as well as human pregnancies both systemicallyand in the uterus48,58,59. However, regulatory T cells seemto be driven by hormonal rather than antigen-dependentmechanisms, as they are also increased in number insyngeneic pregnancies. Depletion of regulatory T cellsleads to failure of pregnancies following allogeneic butnot syngeneic matings, indicating that regulatory T cellsmight regulate damaging allospecific effector T-cellresponses48. Crucially, it is still not established whetherthe failed pregnancies occur because of T-cell reactivityto either trophoblast-cell antigens or to fetal antigens.Furthermore, the effector mechanisms are unclear, as it

has not been shown that uterine T cells can kill murinetrophoblast cells.

Adaptive immune responses in humans and other pri-mates.In primates, placental trophoblast cells encounterthe maternal immune system in two main areas the

villous trophoblast cells interact with the maternal bloodand the extravillous trophoblast cells interact with theuterine tissue. The first area of interaction is betweenthe layer ofsyncytiotrophoblast that overlies the chorionic

villi and is bathed by maternal blood that is delivered bythe spiral arteries into the intervillous space (FIG. 3a). Inhumans, the syncytiotrophoblast is therefore in contact

with the systemic but not the uterine immune com-ponents of the mother. The syncytiotrophoblast expressesno MHC antigens on its surface, which is consistentwith the concept that the placenta is immunologicallyneutral6. Indeed, it has been difficult to demonstrate anysystemic maternal T- or B-cell responses to trophoblastcells (as opposed to fetal cells that cross into the maternalcirculation) during human pregnancy60. Hints that thereare qualitative differences in all systemic T- and B-cellresponses in pregnancy come from the altered clinicalcourse of autoimmune diseases and viral infections dur-ing pregnancy. For example, the symptoms of rheumatoidarthritis (which is T

H1-cell mediated) improve during

pregnancy, whereas those of systemic lupus erythema-tosus (which is T

H2-cell mediated) worsen and this is

presumably caused by the bias away from TH1- towards

TH2-cell responses61,62. Notably, these responses are to all

antigens, not just to those expressed by components ofthe feto-placental unit. This shift to T

H2-cell responses in

pregnancy might be an epiphenomenon that is secondaryto the flux of hormones and cytokines that are secreted

into the circulation, because there is no evidence that itis essential for pregnancy success in humans. Overall,it is improbable that classical allogeneic rejection of the

villous placenta is responsible for reproductive failure.The second area of contact is between invasive extra-

villous trophoblast cells and immune cells in the decidua.In contrast to the syncytiotrophoblast, extravillous tropho-blast cells express an unusual combination ofHLA-C,HLA-G and HLA-E molecules6. High level expressionof HLA-G is restricted to the trophoblast cells thatinfiltrate the uterus. The polymorphic HLA-A andHLA-B molecules, which initiate allograft rejection, arenot expressed, and HLA-C is the only HLA moleculeexpressed by trophoblast cells that shows any appreciablepolymorphism. In those species that have been studiedin detail, such as humans and mice, there is no largeinflux of T or B cells to the implantation site in normalpregnancies. Any T cells present in failed pregnanciesmight be recruited following the demise of the fetusand the resulting inflammatory changes. As in mice,an important role for T-cell damage to trophoblast cellsinfiltrating the decidua that results in pregnancy loss inhumans has not been established.

So, how are adverse maternal T-cell responses topaternally expressed HLA-C molecules or other unidenti-fied trophoblast-cell antigens avoided? MHC-class-II-expressing macrophages and dendritic cells (DCs) are

present in the placental bed and could present trophoblast-cell-derived antigens indirectly to the maternal immunesystem63. These decidual antigen-presenting cells mightbe pivotal in the expansion of both CD4+CD25+ and CD8+regulatory T-cell populations that are present in uteroduring human pregnancy59,64. Interestingly, the CD8+regulatory T cells in the uterus are not MHC restrictedbut are specific for a member of the carcinoembryonicantigen family, an oncofetal trophoblast molecule, andselectively use the T-cell receptor V964. Another possiblemechanism to explain the lack of uterine T-cell activa-tion in normal pregnancies depends on the high-aviditybinding of HLA-G to leukocyte immunoglobulin-like

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receptors (LILRs) expressed by myelomonocytic cells65.Increased expression ofLILRB1 is associated with theinduction of a tolerogenic population of DCs, which, ina transplantation setting, results in tolerance66,67. Recentdata have indicated that this HLA-G-induced tolerancewas due to decreased MHC class II peptide presentationby the tolerogenic DCs68. The idea that the placenta itselfis modifying the maternal immune reactivity, locally inthe uterus, through a trophoblast-cell-specific monomor-phic HLA molecule or an oncofetal protein to downregu-late T-cell responses during pregnancy is attractive. In thenon-pregnant endometrium, T-cell responses are normalas evidenced by rapid production of granulomas follow-ing infection of the endometrium withMycobacteriumtuberculosis69.

Of the non-human primates studied, Rhesus monkeys(Macaca mulatta ) express a MHC molecule (Mamu-AG)that has many of the characteristics of HLA-G, includ-ing that of having a soluble variant70. A similar MHCmolecule is also present in baboons71. However, the pat-tern of expression is different, as the baboon MHC-like

molecules are expressed by the syncytiotrophoblast.This might reflect the limited interstitial invasion byextravillous trophoblast cells in these species. The roleof these HLA-G-like molecules in immunomodulationis unexplored.

Uterine NK-cell recognition of trophoblast cells.Predecidual changes in the endometrium and the influxof uterine NK cells, which occur before implantation, areunique to primates. Given the lack of evidence for T-cellresponses to trophoblast cells, it is compelling to thinkthat uterine NK cells provide the main mechanism bywhich the maternal immune system recognizes tropho-blast cells. In humans, uterine NK cells express an array ofreceptors, some of which are known to bind to the HLAclass I molecules expressed by extravillous trophoblastcells6. Unlike blood NK cells, all uterine NK cells expresshigh levels of the C-type lectin family member CD94NKG2A, which binds to HLA-E resulting in inhibitionof NK-cell cytotoxicity72. All NK cells also express theKIR-family member KIR2DL4, which can bind HLA-G.HLA-G is endocytosed into KIR2DL4-containing endo-somal compartments. The subsequent interaction resultsin upregulation of expression of pro-inflammatory andpro-angiogenic cytokines, indicating a mechanism bywhich the placenta can increase its own blood supply73. Inaddition, any soluble HLA-G molecules in the maternal

circulation could bind KIR2DL4 expressed by blood NKcells and as a result could contribute to the inflammatoryand vascular changes that are characteristic of all preg-nancies74. Therefore, a trophoblast-cell MHC moleculecan signal to the decidual innate immune system throughboth KIR2DL4 on NK cells and LILRB1 (or LILRB2) onmyelomonocytic cells. By alerting two different cell types,HLA-G might be acting as a placental signal that inducespregnancy-specific functions in the uterus.

HLA-C is the only known polymorphic MHC orMHC-like molecule that is expressed by trophoblast cellsand is the dominant ligand for the members of the KIRfamily of receptors that have two immunoglobulin-like

domains (KIR2D). These might be activating (KIR2DS)or inhibitory (KIR2DL) receptors. KIR haplotypes com-prise two groups, A and B, the main difference beingthat there are more activating receptors in the B hap-lotype75. In any pregnancy, the maternal KIR genotypecould be AA (no activating KIR) or AB/BB (presenceof between one and five activating KIRs). The HLA-Cligands for KIRs on trophoblast cells can belong to twogroups, HLA-C1 and HLA-C2, which are defined bya dimorphism at position 80 of the 1 domain. Thismaternalfetal immunological interaction that occursat the site of placentation, therefore involves two poly-morphic gene systems, maternal KIRs and fetal HLA-Cmolecules. NK-cell function is therefore likely to vary ineach pregnancy. Some KIR/HLA-C combinations mightbe more favourable to trophoblast-cell invasion, result-ing in a greater increase in in utero placental blood flowthan other combinations as a result of the overall signalsthat the NK cell receives.

This hypothesis is supported by a recent study show-ing that the occurrence of pre-eclampsia is associated

with an increased frequency of maternal KIRs of theAA genotype but only when this is combined withthe presence of an HLA-C2 allotype in the fetus76. Howdo these genetic results translate to functional eventsat the implantation site? The KIR phenotype of uterineNK cells is skewed towards increased expression of theKIR2D receptors that bind to the two HLA-C groupscompared with blood NK cells77. Stronger inhibitory sig-nals are delivered to NK cells by the HLA-C2KIR2DL1interaction compared with the HLA-C1KIR2DL2 orHLA-C1KIR2DL3 interactions75. We propose that inpregnancies with a fetus that expresses HLA-C2, thestrong inhibitory signal needs to be overcome for suf-ficient trophoblast-cell invasion to occur and this willhappen if the mother has activating KIRs, otherwise thefeto-placental blood supply will be inadequate. Whentrophoblast cells are homozygous for HLA-C1, there isonly weak inhibition that does not require the presenceof compensatory activating KIRs. To summarize, uterineNK cells do express KIRs that are specific for HLA-Cligands expressed by trophoblast cells, and geneticpolymorphisms of this system can affect reproduc-tive outcome. This predicts that there is strong selec-tion against those HLA-CKIR combinations that aredetrimental to reproduction. Population analysis hasdemonstrated reciprocal frequencies of HLA-C2 andKIR AA genotypes in different human populations76.

Because they segregate independently, a situation mighthave evolved so that pregnancies with HLA-C2KIR AAcombinations (which are associated with pre-eclampsia)do not occur too frequently in any population. However,individuals must not only reproduce but their offspringneed to survive, and balancing selection (which wouldmaintain the gene frequencies) for KIRs and HLA-Cmight come from immune recognition of pathogens78.

Comparison of the human KIR-gene family with thatof chimpanzees, gorillas, bonobos, orangutans and rhesusmacaques indicates that this system is rapidly evolving7983.With regard to placentation, the lineage of KIR genes thatrecognizes MHC-C molecules is only present in apes.

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In rhesus macaques, in which there is a well-defined tro-phoblast-cell shell, minimal infiltration of the decidualstroma and modification of the arteries only by endovas-cular trophoblast cells, MHC-CKIR interactions do notoccur80. MHC-C is only present in half of orangutans andall the alleles belong to the C1 group. In this species, theKIR genes that are predicted to bind to MHC-C wouldall bind the C1 epitope and there are none specific forMHC-C2 (REF. 81). Chimpanzees, gorillas and bonoboshave KIRs that can bind MHC-C of both C1 and C2groups. This shows species-specific co-evolution of bothKIR and MHC-C genes. The MHC-C C1 group, whenin combination with the KIR AA genotype, seems to beneutral as far as the risk of pre-eclampsia is concerned.This is the only combination that occurs in orangutansand so the strong KIR inhibition mediated by MHC-CC2 is a later addition in the great apes. This has possiblyarisen as a result of selective pressures imposed by theincreasingly dangerous placental invasion.

Concluding remarks

Although structural variations in eutherian placentaeprovide endless fascination for comparative anatomists,they can present difficulties when extrapolating resultsfrom animal studies to human pregnancy. Structuralcharacteristics are important in the study of pregnancyimmunology because the more invasive the placenta,the greater the interaction it is likely to have with thematernal immune system. Placental anatomical varia-tion is reflected in the considerable difference in the generepertoire for both immunity and reproduction in themouse and human genome84. The two gene systems thathave diverged most are the MHC genes and the NK-cell-receptor genes and these now seem to have importantroles in both reproduction and immunity.

Although the immunological characteristics of humanplacentation are fairly well documented, the situation inother species, including mice, is still sparse and often con-flicting. It is clear that the placenta is not immunologicallyneutral because MHC antigens are expressed by tropho-blast-cell subpopulations in most of the species studied. Inhumans, these are ligands for receptors on innate immunecells, and whether MHC-restricted T-cell recognition oftrophoblast cells occurs in normal or abnormal pregnan-cies is unclear. It will be a challenge to determine howregulatory T cells, HLA-G, oncofetal antigens and otherpotential mechanisms to avoid adverse T-cell responsesto trophoblast cells are generated and whether failure ofT-cell control ever does have a role in pregnancy failure.

The role of NK cells in pregnancy is also uncertain,although in humans, there is an indication that HLA-CKIR interactions between trophoblast cells and NK cellsdo regulate the depth of trophoblast-cell invasion. It is alsoprobable that there is a direct effect of uterine NK cellson spiral artery structure and function (possibly modifiedby soluble trophoblast-cell-derived factors). The relative

importance of interactions between the three components uterine NK cells, trophoblast cells and arteries prob-ably vary in different species. Whatever mechanisms areinvolved, the maternal immune system must providea balance between the need for fetal intrusion into themothers resources and the need to protect the motherfrom excessive fetal greed. In studying this, the view ofthe uterus as a privileged site is no longer valid, as allanatomical sites have unique immune features and thisapplies particularly to mucosal surfaces. The comparisonof the uterine mucosa to the gut or the nose (in whichCD56hi NK-like cells are also frequently found) wouldseem far more informative than to the traditional sites ofimmune privilege, such as the eye, brain or testis.

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AcknowledgementsThe authors thank D. Antczak, G. Burton, S. Ellis, S. Murphy,

P. Parham, R. Pijneneborg, A. Sharkey and P. Wooding for

helpful comments.

Competing interests statementThe authors declare no competing financial interests.

DATABASESThe following terms in this article are linked online to:

Entrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

CD40 ligand | CD80 | CD86 | CD95L | HLA-A | HLA-B | HLA-C |

HLA-E | HLA-G | KIR2DL4 | LILRB1 | NKG2A | PDL1

Access to this links box is available online.

R EV IEW S

594 | AUGUST 2006 | VOLUME 6 www nature com/reviews/immunol

immunology of placenta ti on

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