The Placenta: Your New Favourite Immune Organ

“Yet, in spite of being the star of the show, the placenta has never quite managed to gain the attention it deserves.” – Y.W. Loke 

The placenta is a unique, temporary organ that exists only for 9 months. Its sole purpose is to support the growing fetus – or is it? Over the last 20 years, research has shown that the placenta is more than a passive mediator of nutrient and gas transport; it is an active immune organ. In fact, the placenta has to solve one of biology’s most complicated challenges: protecting a fetus that is genetically half-foreign from immune attack while also protecting it from harmful pathogens. 

Pregnancy and the placenta: an immunological puzzle

The growing fetus inherits half of its DNA from the father, making it immunologically distinct from the mother. Normally, the immune system looks for foreign invaders and launches an attack to get rid of them, yet pregnancy proceeds without attack on the fetus. This process is mediated by the placenta! For a successful embryo to form, fetal cells must first attach and implant into the maternal lining of the uterus, known as the decidua. The placenta is then formed from specialized fetal cells, known as trophoblast cells, that invade into the decidua. Together, fetal trophoblast cells and maternal immune cells dilate maternal blood vessels in the decidua, known as spiral arteries. This process decreases the force of the arterial blood flow and maximizes the volume of the maternal blood that bathes the placenta to support the growing fetus.

What do immune cells really do in the placenta?

The invasive nature of fetal trophoblasts without any attack by immune cells initially appears to defy the basic tenets of immunology. In pregnancy, instead of provoking an attack by the immune system, trophoblast cells communicate with maternal immune cells to promote maternal tolerance – acceptance of the foreign fetus. Decidual natural killer (NK) cells are the largest population of maternal immune cells at the maternal-fetal interface. Unlike the NK cells circulating in our blood that are highly cytotoxic (toxic to cells) and seek to kill pathogens, decidual NK cells are reprogrammed during pregnancy. Rather than killing cells, they help build the placenta by promoting blood vessel development, driving spiral artery remodelling, and promoting trophoblast invasion.

Macrophages are also abundant in the decidua. Typically, decidual macrophages are anti-inflammatory and promote spiral artery remodelling. These cells also act as “cleaners” of the placenta by helping to clear dead trophoblast cells that might activate inflammatory pathways. Fetal macrophages, also known as Hofbauer cells, are present from early stages of pregnancy, and play an important role in maintaining an anti-inflammatory environment. Macrophages act as the primary line of defense against infection for invading microbes in the placenta!

T cells are also present in the decidua, primarily in the form of regulatory T cells. They help to prevent excessive immune responses against the fetus. Reduced numbers of these regulatory cells have been linked to infertility, recurrent spontaneous abortion, and many other pregnancy complications.

Another important way that tolerance is maintained is via specific molecules, which act as “do-not-attack” signals. One such molecule, known as HLA-G, is expressed on the fetal trophoblast cells that invade the decidua, and binds to receptors found on decidual NK cells that inhibit their killing function. 

Defending against infection

Just because the placenta promotes maternal immune cell tolerance does not mean it lets everything get by!

The human placenta is bathed in maternal blood and is ultimately exposed to any and all harmful pathogens found in the blood. In order to protect the growing baby from infection, the placenta must delicately balance the immune response against foreign pathogens to ensure no harm is done to the fetus. 

One way this is achieved is through the architecture of the placenta. The outermost layer of the human placenta is a single multinucleated cell layer that interacts with the maternal blood. This cell layer, referred to as the syncytiotrophoblast (STB), lacks any gaps or junctions between cells that would otherwise allow for pathogens to pass through. 

The placenta also secretes antiviral molecules that work to restrict viral infections. Specifically, the STB layer continuously secretes type III interferons, molecules that stimulate cells to produce anti-viral factors. In a study of pregnant mice, researchers found that mice lacking interferons were more likely to have fetuses that were infected with Zika virus. Placental trophoblast cells also express pathogen recognition receptors, which can detect invading microbes and produce antimicrobial factors to limit infection.

Finally, the placenta also plays an important role in the transport of passive immunity to the fetus. Beginning at the 16th week of pregnancy, the placenta actively transports protective antibodies in the form of immunoglobulin G (IgG) via receptors for IgG on the surface of the STB. This transport increases over the course of pregnancy so that at term, the fetal bloodstream has a greater concentration of maternally derived IgG than the mother does!

The placental immune environment is not static!

Pregnancy is not one immune state. Despite the importance of maintaining fetal tolerance, the levels of inflammation over the course of pregnancy look somewhat like a rollercoaster. Early pregnancy requires carefully controlled inflammation to ensure there is proper remodelling of spiral arteries without rejection of the developing embryo. Mid-pregnancy emphasizes tolerance and fetal growth and is dominated by an immune-regulatory environment to ensure careful immune activation. Just before birth, the protective tolerance wanes and a localized inflammatory response in the uterus begins to initiate labour!

Why the placenta deserves more attention?

Proper placental immune function is absolutely vital for a healthy pregnancy. Disrupted immune responses at the maternal-fetal interface have been linked to a number of pregnancy complications, including preeclampsia, fetal growth restriction, miscarriage, and congenital infections. The placenta is one of the most sophisticated temporary organs in biology. It simultaneously acts as a barrier, transport system, immune regulator, and defender. Despite the difficulty of maintaining two contradictory jobs, the placenta performs them remarkably well, making it one of the most fascinating organs most people rarely think about.