In everyday moments, such as sipping coffee or enjoying an ice cream cone, the human body performs a biological miracle. It processes food without harming health through a process called oral tolerance. But how does the body decide between tolerance and rejection?
A groundbreaking study led by Stanford University scientists has identified new protein fragments that signal gut immune cells to tolerate certain foods. The research, published in Science Immunology in March 2026, was conducted by Jamie Blum, PhD, and Elizabeth Sattely, PhD. These protein segments, known as epitopes, were found in soybean, corn, and wheat, and they interact with regulatory T cells to determine the body’s tolerance or rejection of these foods. This discovery marks a significant advancement in understanding food tolerance and could inform future immunotherapies for food allergies.
Understanding the Mechanism of Food Allergies
Food allergies affect approximately 6% of young children and 3% to 4% of adults. Researchers have been striving to understand the triggers of allergic reactions to foods that should be safe. Their efforts have revealed specific proteins in common allergens, such as peanuts and eggs, that cause adverse immune responses. These proteins are recognized by antibodies, which activate mast cells and basophils, two fast-acting inflammatory cells of the immune system.
While scientists have largely understood the “how” of immune reactions during allergies, the “what” of immune reactions during tolerance has remained elusive. Prior research has shown that regulatory T cells play a crucial role in tolerance, with their anti-inflammatory and immune-suppressive functions. However, the specific proteins that prompt this non-reaction were unknown until now.
Discovery of Tolerated Proteins
The study began with a simple bowl of mouse chow. Researchers screened regulatory T cells from mice on a normal diet to identify what these cells attached to, then traced them back to specific parts of the chow. They discovered three epitopes recognized by regulatory T cells, each from corn, wheat, and soybean proteins. Notably, these epitopes are from seed proteins, indicating that these abundant plant proteins are commonly recognized by the immune system’s tolerance mechanisms.
The most abundant T cells were reactive to the corn epitope, which aligns with the fact that corn is not a common allergen. The identification of a soybean epitope is particularly exciting, given that soy is a major allergen in humans. Blum noted that the mammalian receptor interacting with the soybean epitope also interacts with sesame, explaining cross-tolerance, where tolerance to one food infers tolerance to another.
Potential for Future Therapies
With the identification of these new epitopes, researchers explored additional questions, such as the location of regulatory T cells and their performance in inflamed versus healthy environments. Using mice and cell culture models, they found that regulatory T cells primarily reside in the gut and their activities vary based on the environment, either reducing inflammation or maintaining its absence.
These findings add a new dimension to our understanding of oral tolerance. Regulatory T cells have long been considered a promising route for immunotherapy in severe food allergies. It may one day be possible to create regulatory T cells pre-programmed to tolerate certain foods, dampening immune responses to common allergens.
“Diet is our most intimate interaction with our environment,” says Blum. “Correctly recognizing foods as safe creates an anti-inflammatory environment to support nutrient acquisition and prevent allergy. Our research advances scientific understanding of the major dietary allergens and points us toward future therapeutic interventions that could redirect allergic and autoimmune states.”
Looking ahead, researchers are eager to see their protein mapping workflow adapted to humans. The reagent they developed is now available for others to use, paving the way for new insights into regulatory T cell-mediated oral tolerance.
The study, titled “Identification and Characterization of Dietary Antigens in Oral Tolerance,” was authored by Blum JE, Kong R, Schulman EA, et al. and published in Sci Immunol. The findings represent a promising step towards the development of therapies that could one day eliminate food allergies.
