Science - USA (2019-08-30)

INSIGHTS | PERSPECTIVES

862 30 AUGUST 2019 • VOL 365 ISSUE 6456 sciencemag.org SCIENCE

PERSPECTIVES

IMMUNOLOGY

The immunological code of pregnancy

Maternal immune cells interact with the placenta and influence pregnancy complications

By Francesco Colucci

V

arious factors contribute to the hy-

pertensive placental disease pre-

eclampsia, fetal growth restriction

(FGR), spontaneous abortion, pre-

term labor, and stillbirth. Some of

these problems are due to placental

dysfunction ( 1 ). The placenta attaches to

and invades deep into the decidua, the spe-

cialized uterine mucosa that is rich in ma-

ternal immune cells. Because the placenta

is formed from the fetus and contains ge-

netic material from another individual (the

father), it should be targeted by the mater-

nal immune system but it usually is not. By

understanding the interactions between the

placenta and the maternal immune system,

interventions to improve pregnancy out-

comes could be developed.

An example of how immunological in-

compatibility can cause pathology is rhe-

sus (Rh) disease. Immunity is passed from

mother to fetus through neonatal Fc recep-

tors on placental cells (trophoblasts) that

bind immunoglobulin G (IgG) antibodies.

These maternal antibodies protect neonates

while their own antibodies are developing.

But in blood group–mismatched pregnan-

cies, maternal antibodies against the RhD

antigen made by Rh-negative mothers are

also transported through the placenta and

destroy Rh-positive fetal red blood cells,

causing severe anemia. Understanding the

basic mechanisms of this fetal disease has

led to a successful preventive treatment with

immunotherapy.

Interactions within the decidua are im-

portant to understand most pregnancy com-

plications (see the figure). The placenta is

formed from embryonic trophoblast cells,

and their invasion into the decidua ensures

that the developing embryo acquires nutri-

ents and oxygen from maternal blood. The

interactions between maternal decidual im-

mune cells and fetal trophoblast cells trans-

forms uterine arteries into flaccid, large

conduits, called spiral arteries, where cir-

culation is slowed down. Appendices (villi)

of the placenta bathe in the blood within

spiral arteries, absorbing nutrients and ex-

changing gases needed for fetal growth.

Shallow trophoblast invasion is associated

with preeclampsia, FGR, and miscarriage ( 1 ),

whereas excessive invasion causes placenta

accreta, which can lead to fatal hemorrhage

during birth. The cross-talk between tropho-

blast and immune cells in the decidua is key

to the depth of trophoblast invasion ( 2 ).

Obstetrics research is challenging because

of the constantly changing nature of tissues

and the difficulty in accessing them, espe-

cially during the first trimester. An additional

challenge is to decode the function of tissue-

resident immune cells, which may adapt to

specific microenvironments. Moreover, each

mammalian species has evolved its own

placentation process. The placenta in mice

and humans is hemochorial, meaning that

extravillous trophoblast (EVT) cells invade

the decidua, although the degree of invasion

is greater in humans. Another similarity is

that cells of the innate immune system are

most abundant in the decidua compared to

other tissues. These include decidual natural

killer (dNK) cells and macrophages, as well

as dendritic cells (DCs) and T cells, including

immunosuppressive regulatory T cells (Tregs)

( 2 ). In mice, Tregs are induced at conception

in the female reproductive tract by cytokines

in semen, they expand in subsequent preg-

nancies, and their depletion causes abortion.

In humans, Tregs are fewer and less functional

in preeclampsia ( 3 ). The role of decidual Tregs

may not be to suppress immune responses,

because maternal immune cells that might

cause placental dysfunction by targeting pa-

ternal antigens and must therefore be con-

trolled by Tregs have never been identified.

Directly or indirectly through modulating

the functions of dNK cells, macrophages,

and DCs in the decidua, Tregs may partici-

pate in tissue remodeling, as demonstrated

in adipose tissue, muscle, and intestine ( 4 ).

They may also regulate the transformation

of the endometrial lining of the uterus into

decidua (decidualization), implantation, and

vascular adaptations during placentation.

Exaggerated inflammation during preg-

nancy in response to infections such as in-

fluenza can be fatal to mother and fetus.

Placental ischemia triggers systemic inflam-

matory responses of maternal endothelial

cells (which line blood vessels), leading to

hypertension in preeclampsia. However, in-

flammation and the innate immune system

might have become integral to the necessary

destruction and regeneration of the uterine

mucosa during the menstrual cycle and in

pregnancy. Immunological mechanisms that

had originally evolved to destroy and repair

might have been co-opted to participate in

successful placental invasion. Traditional

ideas about immunity and pregnancy sug-

gest that immunological tolerance of non-self

tissues must prevail and, for the pregnancy to

succeed, maternal immune cells must be pre-

vented from responding to paternal antigens

in the fetus. The emerging idea is that the

invasive type of placentation in humans and

mice has coevolved with the immune system

to both maximize the benefits and minimize

the hazards of cross-talk between trophoblast

and immune cells, rather than avoiding ma-

ternal immune responses in the decidua.

The need for functional immune cells at

the maternal-fetal interface is exemplified by

dNK cells. Although blood NK cells kill vi-

rally infected and cancerous cells, dNK cells

are involved in tissue homeostasis rather

than in killing. In mice, dNK cells are neces-

sary for uterine vascular adaptations during

pregnancy ( 5 ). In humans and mice, dNK

cells seem to participate in controlling tro-

phoblast invasion and transforming uterine

blood vessels into spiral arteries. Genetic

evidence in humans and mice suggests that

excessive inhibition of dNK cell function im-

pedes both decidual arterial remodeling and

fetal growth ( 6 ). Maternal dNK cells and fetal

trophoblast cells establish intimate connec-

tions through receptor-ligand interactions,

and these may be the key to cracking the

immunological code of pregnancy. The main

determinants of immune tolerance—the ex-

tremely variable human leukocyte antigen

(HLA) molecules that present antigens to T

cells—are not expressed by the outer layer of

the placenta (syncytiotrophoblast), thereby

avoiding any possible recognition of paternal

antigens by maternal immune cells. How-

ever, human fetal EVT cells express invari-

able HLA-E and HLA-G, and variable HLA-C,

which can be derived from either parent and

Department of Obstetrics and Gynaecology, University

of Cambridge School of Clinical Medicine and Centre for

Trophoblast Research. National Institute for Health Research

Cambridge Biomedical Research Centre, Cambridge CB2 0SW,

UK. Email: [email protected]

Published by AAAS