A decade ago, a clinical trial in the U.K. notably 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, a study by researchers at Memorial Sloan Kettering Cancer Center (MSK) has found that a population of cells known as Thetis cells (TC) may provide the answer as to why. The team’s preclinical study results indicate that the TC IV subset of this recently discovered class of immune cells, which was first described by MSK researchers in 2022, plays an essential and previously unknown role in suppressing inflammatory responses to food. 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 as the Ara h proteins found in peanuts (though they weren’t specifically tested in the study) or the ovalbumin found in eggs.
The study, in mouse models, also points to a critical window in the early months of life for training the immune system not to overreact to food allergens—which is referred to as “oral tolerance.” The researchers, headed by physician-scientist Chrysothemis Brown, MD, PhD, say the study also opens the door to new therapeutic possibilities. “This is a great example of how clinical studies can reveal clues to fundamental mechanisms in biology,” noted Brown, who is a senior author of the team’s published paper in Science, titled, “A wave of Thetis cells imparts tolerance to food antigens early in life.” Brown added, “These new understandings can pave the way for new treatment strategies for food allergies, which are desperately needed.” In their paper, the team concluded, “Our findings indicate that TC IV may represent a therapeutic target for the treatment of food-associated allergic and inflammatory diseases.”
The research was led by co-first authors pediatric hematologist-oncologist Vanja Cabric, MD, and research assistant Yollanda Franco Parisotto, PhD.
“The immune system must establish and maintain tolerance to harmless orally ingested food proteins to prevent the onset of inflammatory diseases such as food allergy or celiac disease,” the authors explained. Thetis cells are a type of antigen-presenting cell (APC), 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. The authors further noted, “Antigen-presenting cells (APCs) play a role in determining the nature of the immune response to intestinal antigens by promoting the differentiation of naïve CD4+ T cells into diverse proinflammatory T helper (TH) cell subsets, that mediate distinct types of inflammation, or peripherally-induced Foxp3+ regulatory T (pTreg) cells, that suppress inflammatory responses to harmless microbiota or food antigens.”
Oral tolerance has been widely studied in adult mice, the team stated, but “dysregulated responses to food antigens, including IgE-mediated food allergy, food protein-induced inflammatory enterocolitis, and pediatric celiac disease, present almost exclusively in infancy or childhood, when food antigens are first encountered.”
Previous research led by 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,” said Brown, whose lab is in MSK’s Human Oncology and Pathogenesis Program (HOPP). “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.”
Thetis cells are so named 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.
For their reported study, 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 (TC IV), 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. “… we found that a subset of Thetis cells, TC IV, is required for food-specific pTreg cell differentiation,” the investigators wrote.
“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,” Cabric added.
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. “A wave of TC IV differentiation in the peri-weaning period was associated with a window of opportunity for enhanced pTreg generation in response to food antigens,” the team noted in their paper.
“The number of regulatory T cells that are generated during this developmental wave in young mice was about eightfold higher than in adult mice,” Parisotto stated. “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, Brown added. Introducing food allergens early on 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.
This new mechanistic understanding of food tolerance opens new therapeutic possibilities, Brown suggested. “We’ve shown that there is a window for generating stronger tolerance, which is mediated by Thetis cells … 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. “The presence of TCs in humans suggests potential therapeutic value in targeting antigens to TC IV for promotion of immune tolerance in settings of food allergy and inflammatory diseases,” the team reported.
Along with the increased abundance of Thetis cells during early life, the subset of Thetis cells, called Thetis cell IV, that induce tolerance was 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,” Brown added. “We speculate that layered hematopoiesis ensures a preponderance of TCs and tolerance to dietary antigens during early life, and contributes to the tolerogenic properties of mesenteric lymph nodes,” the investigators wrote. “The paucity of TC IV in skin-draining lymph nodes may account for the increased incidence of food allergy when food-associated antigens are encountered via the topical route in patients with altered skin barrier function, most commonly due to eczematous inflammation.”
Further, by shedding new light on how Thetis cells work and how they participate in the development of immune responses early in life, the Brown lab scientists are getting new insights into how they may influence the immune response to early childhood cancers.
The post Immune Cell Type Linked to Oral Tolerance and Childhood Food Allergies appeared first on GEN - Genetic Engineering and Biotechnology News.
Now, a study by researchers at Memorial Sloan Kettering Cancer Center (MSK) has found that a population of cells known as Thetis cells (TC) may provide the answer as to why. The team’s preclinical study results indicate that the TC IV subset of this recently discovered class of immune cells, which was first described by MSK researchers in 2022, plays an essential and previously unknown role in suppressing inflammatory responses to food. 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 as the Ara h proteins found in peanuts (though they weren’t specifically tested in the study) or the ovalbumin found in eggs.
The study, in mouse models, also points to a critical window in the early months of life for training the immune system not to overreact to food allergens—which is referred to as “oral tolerance.” The researchers, headed by physician-scientist Chrysothemis Brown, MD, PhD, say the study also opens the door to new therapeutic possibilities. “This is a great example of how clinical studies can reveal clues to fundamental mechanisms in biology,” noted Brown, who is a senior author of the team’s published paper in Science, titled, “A wave of Thetis cells imparts tolerance to food antigens early in life.” Brown added, “These new understandings can pave the way for new treatment strategies for food allergies, which are desperately needed.” In their paper, the team concluded, “Our findings indicate that TC IV may represent a therapeutic target for the treatment of food-associated allergic and inflammatory diseases.”
The research was led by co-first authors pediatric hematologist-oncologist Vanja Cabric, MD, and research assistant Yollanda Franco Parisotto, PhD.
“The immune system must establish and maintain tolerance to harmless orally ingested food proteins to prevent the onset of inflammatory diseases such as food allergy or celiac disease,” the authors explained. Thetis cells are a type of antigen-presenting cell (APC), 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. The authors further noted, “Antigen-presenting cells (APCs) play a role in determining the nature of the immune response to intestinal antigens by promoting the differentiation of naïve CD4+ T cells into diverse proinflammatory T helper (TH) cell subsets, that mediate distinct types of inflammation, or peripherally-induced Foxp3+ regulatory T (pTreg) cells, that suppress inflammatory responses to harmless microbiota or food antigens.”
Oral tolerance has been widely studied in adult mice, the team stated, but “dysregulated responses to food antigens, including IgE-mediated food allergy, food protein-induced inflammatory enterocolitis, and pediatric celiac disease, present almost exclusively in infancy or childhood, when food antigens are first encountered.”
Previous research led by 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,” said Brown, whose lab is in MSK’s Human Oncology and Pathogenesis Program (HOPP). “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.”
Thetis cells are so named 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.
For their reported study, 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 (TC IV), 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. “… we found that a subset of Thetis cells, TC IV, is required for food-specific pTreg cell differentiation,” the investigators wrote.
“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,” Cabric added.
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. “A wave of TC IV differentiation in the peri-weaning period was associated with a window of opportunity for enhanced pTreg generation in response to food antigens,” the team noted in their paper.
“The number of regulatory T cells that are generated during this developmental wave in young mice was about eightfold higher than in adult mice,” Parisotto stated. “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, Brown added. Introducing food allergens early on 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.
This new mechanistic understanding of food tolerance opens new therapeutic possibilities, Brown suggested. “We’ve shown that there is a window for generating stronger tolerance, which is mediated by Thetis cells … 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. “The presence of TCs in humans suggests potential therapeutic value in targeting antigens to TC IV for promotion of immune tolerance in settings of food allergy and inflammatory diseases,” the team reported.
Along with the increased abundance of Thetis cells during early life, the subset of Thetis cells, called Thetis cell IV, that induce tolerance was 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,” Brown added. “We speculate that layered hematopoiesis ensures a preponderance of TCs and tolerance to dietary antigens during early life, and contributes to the tolerogenic properties of mesenteric lymph nodes,” the investigators wrote. “The paucity of TC IV in skin-draining lymph nodes may account for the increased incidence of food allergy when food-associated antigens are encountered via the topical route in patients with altered skin barrier function, most commonly due to eczematous inflammation.”
Further, by shedding new light on how Thetis cells work and how they participate in the development of immune responses early in life, the Brown lab scientists are getting new insights into how they may influence the immune response to early childhood cancers.
The post Immune Cell Type Linked to Oral Tolerance and Childhood Food Allergies appeared first on GEN - Genetic Engineering and Biotechnology News.