ORAL tolerance to dietary proteins may be shaped by specific plant-derived seed storage proteins, according to new research that identified previously unknown food antigens recognised by immune-regulating cells in the gut.
The immune system is constantly exposed to food-derived molecules, yet harmful immune reactions to dietary proteins are relatively rare. This is largely due to oral tolerance, a process in which intestinal immune mechanisms suppress inflammatory responses to harmless food components. Failures in this system can contribute to conditions such as food allergies or coeliac disease.
While food allergens have been extensively characterised, the dietary proteins responsible for promoting oral tolerance have remained largely unknown. Identifying these tolerance-inducing antigens is important for understanding how the immune system distinguishes harmless foods from harmful threats.
Seed Storage Proteins Linked to Oral Tolerance
In the new study, researchers investigated how intestinal regulatory T cells (Treg cells) recognise dietary proteins that promote oral tolerance. These specialised immune cells suppress excessive immune responses and play a critical role in maintaining immune balance in the gastrointestinal tract.
To identify the food antigens recognised by these cells, the team analysed T cell receptors derived from murine intestinal Treg cells. The analysis revealed that several seed storage proteins from staple crops, including maize, wheat, and soy, were prominent targets of food-responsive Treg cells.
One protein in particular, the maize seed storage protein α-zein, emerged as the most frequently recognised antigen. Researchers mapped the immune response to specific epitopes within the C-terminal region of α-zein.
Using a major histocompatibility complex tetramer loaded with the α-zein peptide, the investigators demonstrated that zein-specific T cells were predominantly intestinal Treg cells. These cells appeared during the weaning period and expanded to represent up to 2% of the peripheral Treg cell pool.
Dietary Exposure Shapes Immune Responses
Functional experiments further showed that α-zein–specific Treg cells suppressed naïve T cell proliferation when exposed to the antigen, confirming their role in maintaining oral tolerance.
The researchers also explored how dietary exposure influenced immune responses during inflammatory conditions. Mice previously exposed to the dietary antigen displayed a reduced immune response during various inflammatory challenges, suggesting that gut-resident Treg cells recognising food proteins may help regulate systemic immune activity as well as intestinal immunity.
The findings highlight seed storage proteins as a previously undescribed class of dietary antigens capable of promoting immune tolerance. By identifying specific food-derived molecules that educate the immune system, the research offers new insight into how tolerance to dietary proteins develops early in life.
It is worth noting that the study was conducted in mice, and further research will be required to determine whether similar mechanisms operate in humans. If confirmed, understanding the dietary drivers of oral tolerance could ultimately help inform strategies to prevent food allergies and other immune-mediated gastrointestinal diseases.
Reference
Blum JE et al. Identification and characterization of dietary antigens in oral tolerance. Sci Immunol. 2026; DOI:10.1126/sciimmunol.aeb4684.
Featured image: Mikhailov Studio on Adobe Stock
