Thetis cells, a class of immune cells first described in 2022, play an essential and previously unknown role in suppressing inflammatory responses to food, a new study finds.
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A decade ago, a clinical trial in the U.K. famously showed that children who were exposed to peanuts in the early months of life had reduced risk of developing a peanut allergy compared with children who avoided peanuts.
Now, researchers at Memorial Sloan Kettering Cancer Center (MSK) have a likely answer as to why that's the case: Thetis cells.
This recently discovered class of immune cells, which were first described by MSK researchers in 2022, plays an essential and previously unknown role in suppressing inflammatory responses to food, according to findings published May 15 in Science, one of the world's premier scientific journals.
Moreover, the study, which was conducted in mouse models, points to a critical window in the early months of life for training the immune system not to overreact to food allergens -- what scientists call "oral tolerance."
The study also opens the door to new therapeutic possibilities, the researchers say.
"This is a great example of how clinical studies can reveal clues to fundamental mechanisms in biology," says physician-scientist Chrysothemis Brown, MD, PhD, the study's senior author. "These new understandings can pave the way for new treatment strategies for food allergies, which are desperately needed."
The research was led by co-first authors from the Brown Lab: pediatric hematologist-oncologist Vanja Cabric, MD, and research assistant Yollanda Franco Parisotto, PhD.
Thetis Cells Train the Immune System To Tolerate Helpful Outsiders
Thetis cells are a type of antigen-presenting cell, whose job is to present foreign substances (antigens) to other immune cells. Antigen-presenting cells must educate the immune system. These cells provide signals that tell the immune system to attack foreign bacteria and viruses -- or instruct it to tolerate harmless proteins in the foods we eat.
Previous research led by Dr. Brown and immunologist Alexander Rudensky, PhD, Chair of the Immunology Program at MSK's Sloan Kettering Institute, identified a window in early life where a "developmental wave" of Thetis cells within the gut creates an opportunity for developing immune tolerance.
"We previously showed that Thetis cells train the immune system not to attack the helpful bacteria in the digestive system. So we wondered whether these cells might also be important for preventing inflammatory responses to food, and whether the increased abundance of the cells during early life would result in increased protection against food allergy," says Dr. Brown, whose lab is in MSK's Human Oncology and Pathogenesis Program (HOPP).
The new study found that Thetis cells not only help to broker peace accords with "good" bacteria, but also with proteins in foods that can act as allergens -- such the Ara h proteins found in peanuts (though they weren't specifically tested in the study) or the ovalbumin found in eggs.
Thetis cells got their name because they share traits with two different types of antigen-presenting cells: medullary thymic epithelial cells and dendritic cells -- just as Thetis in Greek mythology had shape-shifting attributes.
A Key Role for Gut-Draining Lymph Nodes
The research team used a variety of genetically engineered mouse models to investigate oral tolerance. They attached a fluorescent dye to ovalbumin -- a protein found in eggs and a common allergen -- in order to visualize which cells in the gut interacted with it.
And this showed that a subset of Thetis cells -- the same ones that regulated tolerance to healthy gut bacteria -- took up the protein. This allowed Thetis cells to program another type of immune cell called regulatory T cells to suppress the immune response to the egg protein, essentially telling the body it was safe.
"This process is often studied in adult models, but by examining what happens when mice first encounter food proteins at the time of weaning, we could see which specific cells were critical to generating tolerance to food during early life," Dr. Cabric says.
Although Thetis cells could also induce tolerance throughout life, there was a significant difference in the immune response when the egg protein was introduced later.
"The number of regulatory T cells that are generated during this developmental wave in young mice was about eightfold higher than in adult mice," Dr. Parisotto says. "And once established, this tolerance is long-lasting."
One might imagine this as a tug-of-war between the gas pedal of the immune system and the brakes, Dr. Brown adds. When food allergens are introduced early on, it enables the body to put the brakes on the immune response much more strongly. But after this developmental wave, when far fewer Thetis cells are present, the brakes aren't always sufficient to overcome the effects of other antigen-presenting cells that act as the gas pedal -- pushing the immune system to mount inflammatory responses to foreign proteins.
New Understandings Suggest New Treatment Strategies
This new mechanistic understanding of food tolerance opens new therapeutic possibilities, Dr. Brown says.
"We've shown that there is a window for generating stronger tolerance, which is mediated by Thetis cells," she says. "What this suggests is that one might develop new strategies to deliver food antigens directly to Thetis cells to promote tolerance, even though they're rarer outside of this developmental window."
While the current study did not examine the oral tolerance process in humans, other researchers have shown that Thetis cells in mice and humans are extremely similar.
Along with the increased abundance of Thetis cells during early life, the subset of Thetis cells that induce tolerance -- called Thetis cell IV -- were very rare outside of gut lymph nodes.
"Not only does this research underscore the consensus within the allergy community about the benefits of early introduction of allergens, but it also explains why, for example, we don't see a similar tolerance develop when the same antigens are delivered through other routes, like the skin," Dr. Brown says.
Further, by shedding new light on how Thetis cells work and how they participate in the development of immune responses early in life, Dr. Brown and her lab are getting new insights into how they may influence the immune response to early childhood cancers.
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