Placenta-Specific Immune Cells and their Delicate Balancing Act

Imagine going your whole life with the same, occasionally changing body (thanks puberty!) only to realize you now need to grow an entirely new organ. For child-bearing individuals, this is exactly what happens during pregnancy. During this time, the body must find a way to not only tolerate a genetically foreign being but also to help it thrive. This requires a complex balancing act of the body’s immune system, which must avoid attacking the developing fetus while at the same time protecting it from potentially harmful infections. Details of this poorly understood process have recently come to light, with new research out of Harvard Medical School revealing an important role of placenta-resident immune cells.

Structure and function of the placenta

The placenta is a vital organ that provides nutrients, oxygen, and a layer of protection to a developing fetus. It is one of few immune-privileged organs, meaning that it can sustain an infection without eliciting an inflammatory immune response. Instead, the placenta utilizes an optimized, more mild immune response to keep both mom and baby safe. It is also the only organ that grows entirely from scratch with every and any pregnancy an individual may have. 

While there is still much that we don’t know about the complexities of placental immunity, decades of research have taught us some basic lessons about how this organ has evolved to exclude pathogens while protecting the growing life inside. It is structured using multiple layers of fetal cells called trophoblasts that have strong immune defense properties. One unique layer of fetal tissue consists of many individual trophoblasts that have fused into one large cell known as a syncytium. Because this cell is fused together, it lacks the small spaces found between normal, unfused cells where many pathogens could slip in, thus making it less vulnerable to infections. The fused syncytium layer also constantly produces beneficial cytokines, or immune messenger molecules, to help ward off any potential pathogens. Different trophoblasts lie underneath, closer to the fetus and remain unfused, working primarily to upkeep the overall placental and syncytium structure as the pregnancy progresses. The outermost layer, called the decidua, is made of unfused maternal cells that function to anchor the placenta and surround it with an army of different immune cells for protection.

Natural killer cells and how they work 

Despite all of these precautions to keep the fetus safe, infections can still occur within the placenta. When pathogens such as bacteria infect host cells, they enter and use the cells as a place to grow and reproduce. This uncontrolled growth can damage host cells and even lead to cell death which, while troublesome for normal tissues, could be catastrophic to a developing pregnancy. To control harmful infections, there are many types of patrolling immune cells throughout our bodies, including a set of cells called peripheral natural killer cells (pNK). These aptly-named cells help protect our bodies from infection by killing pathogens; but, because pathogens hide inside our own cells, the pNKs must often use immune molecules to sacrifice host cells in order to kill the pathogen inside. These molecules, called perforin, granzymes, and granulysin (GNLY), work in harmony to stop infections. Specifically, perforin makes holes in the infected host cell that, at high levels, can lead to cell death but more efficiently allows for granzymes and GNLY to enter the cell. Once inside, granzymes work to kill the infected host cell, thereby stopping the infection in its tracks. For its part, GNLY compliments granzymes by helping to kill the infecting pathogens.  

While this method of halting infections works for parts of the body where cells can easily regrow and replace those killed by the pNKs, inducing cell death in trophoblasts and a developing pregnancy would come with dire consequences including disrupting or even completely stopping the pregnancy. Because of this, we have evolved a similar set of immune cells that are specific to the placenta called decidual natural killer cells (dNK). These cells are equipped with the same three immune molecules as pNKs, but they must strike a delicate balance compared to their peripheral counterparts. Just how these cells, traditionally defined as aggressive, can defend the fetus without damaging the delicate placenta was poorly understood until recently.  

A unique function of placenta-specific immune cells

Scientists from Harvard Medical School confirmed that the placenta-specific dNK cells in question had all of the necessary weapons to kill host cells infected with bacteria; however, these dNK cells were less likely to do so compared to their more generalized pNK counterparts. In this model, scientists specifically looked at bacterial infections in a trophoblast-like cell line to mimic infections that could naturally occur in the placenta. Despite their unwillingness to kill the bacteria-infected cell, the dNKs ended up killing more bacteria overall compared to pNKs, meaning that while dNKs were not harming the all-important trophoblasts, they were still able to clear the infection more effectively.  

How these cells achieved such precise pathogen-only killing required further investigation. Normally, in order for a natural killer cell to deploy its deadly trio of immune proteins, it has to come into contact with an infected host cell and enter an activated state. However, Crespo et al found that the placenta-specific dNKs continually express GNLY regardless of activation state. Theoretically, this could help maintain an antimicrobial environment within the placenta, but in order for GNLY to function, it needs a way to enter an infected host cell. While researchers saw constant GNLY expression in dNKs, perforin expression, and thus the associated cell entry method for GNLY, was lacking. However, since the total number of bacteria was down for infected cells grown with dNKs compared to those grown with pNKs, researchers hypothesized that GNLY was entering bacteria-infected cells without the help of perforin. 

When observing infected trophoblasts and dNKs together under a confocal microscope, scientists noticed something unusual – the dNKs formed nanotubes, or small cell-cell connections with infected trophoblasts at high frequency (Figure 1). Upon further investigation, the researchers were able to determine that these tubes functioned unidirectionally, meaning proteins, specifically GNLY, were only getting transferred from dNKs to infected trophoblasts and not the other way around. However, whether proteins other than GNLY were also being transferred via these tubes is still unknown. The discovery of these nanotubes was a unique finding that explains how GNLY enters infected trophoblasts without the use of cell damaging perforin and illuminates one of the ways dNKs are able to protect the pregnancy without doing harm. 

Figure 1: Differences between dNK and pNK cell clearing of infections. pNKs must first encounter an infected host cell, after which they produce immune molecules perforin, granzymes and GNLY to kill the infection and the infected host cell.  dNKs constantly produce GNLY and, upon encountering an infected host trophoblast, will transfer high amounts of GNLY via nanotubes to kill off the infection while sparing the host cell. Figure created in Biorender 

Animal studies and the broader implications

As their final step, the authors looked to a mouse model of pregnancy. They utilized wild type (or normal) mice which naturally lack GNLY and mice with GNLY genetically added in. When these mice were treated with a high dose of bacteria, most wild type mice had no viable pups and high levels of bacteria throughout the body. Mice with the genetically-added GNLY had a much better chance of successful pregnancies comparatively and a lower number of overall bacteria, especially in the placenta and fetus. This confirms the relevance of GNLY in defending the developing fetus while not harming the delicate and necessary placenta.

This novel phenomenon of GNLY delivery via nanotubes by dNKs to kill harmful bacteria but not the ever-important trophoblasts sheds light on the extremely fine balance of immunity that is achieved at the maternal-fetal interface. Ultimately, the immune system must work to protect the host from things that seek to do it harm, like bacteria, without becoming so active that it harms the host itself. Throw in a developing fetus that is seemingly foreign and things get complicated quickly. However, this work is a prime example of how well-adapted and unique the maternal-fetal immune system must be. Better understandings of this temporary system could in turn help improve pregnancy outcomes in cases of infection, maternal-fetal transmission and inappropriate immune activation.

Journal article: Angela C Crespo et al. “Decidual NK Cells Transfer Granulysin to Selectively Kill Bacteria in Trophoblasts.” Cell September 3, 2020, 182 1125-39; DOI: 10.1016/j.cell.2020.07.019

Cover Image by Raman Oza from Pixabay

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