Dietary Epitopes Drive Oral Tolerance, With Jamie Blum, PhD

New translational research is beginning to clarify a long-standing gap in immunology: which specific food-derived antigens drive oral tolerance. A study identified discrete dietary epitopes from common seed storage proteins that are recognized by intestinal regulatory T (Treg) cells, offering mechanistic insight into how the immune system classifies foods as “safe.”1 In an interview with HCPLive, Jamie Blum, PhD, of the Salk Institute, emphasized that advancing understanding of tolerance is critical to addressing food allergy at its root.

“While we understand more and more about food allergies, we actually know comparably little about oral tolerance,” Blum said. “What is it? How does it develop? So, I think my study is starting to identify what are the protein antigens that are recognized, and if we understand how those antigens are normally seen through the tolerance response, we might be able to apply those same principles to allergy cases to help better prevent food allergies.”

Using murine models fed standard chow, investigators isolated intestinal Treg cells and identified their cognate antigens through T cell receptor (TCR) mapping. The analysis revealed 3 key epitopes derived from seed storage proteins in corn, wheat, and soybean.1 One of the most robust responses was directed against a maize protein, α-zein, a digestion-resistant storage protein.

“When we started the study, I had expected we might find dozens of different epitopes, and it was unexpected and striking that we saw the strong convergence on just 1 protein, which may suggest that a few key proteins in diet are… are garnering most of the immune response,” Blum said. “If you can tune how the immune response sees those proteins, you can set the overall tone for interpretation of the food.”

These proteins are highly abundant and resistant to digestion, allowing prolonged exposure in the gut for immune sampling. As Blum noted, they “resist proteases,” enabling their role in tolerance induction. Clinically, this convergence suggests a small number of dietary antigens may disproportionately shape immune tolerance.

The study also provides insight into the ontogeny of tolerance. Blum and colleagues observed that antigen-specific Treg populations emerge around the time of weaning, coinciding with initial exposure to solid foods.¹ Blum noted that this developmental window aligns with clinical data supporting early allergen introduction for immune tolerance. This paradigm is supported by the Learning Early About Peanut Allergy (LEAP) trial, which demonstrated that early peanut exposure significantly reduces the risk of peanut allergy and informed current guideline recommendations to introduce allergens between 4 and 6 months of age.2

Mechanistically, the identified Treg cells exhibited canonical immunosuppressive functions, including secretion of anti-inflammatory cytokines and inhibition of effector T cell proliferation.1 These cells help maintain immune homeostasis.

An additional finding is the potential for cross-tolerance. The study demonstrated that TCRs recognizing a soybean-derived epitope also responded to structurally similar proteins in other foods, including sesame and quinoa.1 This suggests that exposure to 1 food antigen could confer tolerance to related proteins, even in the absence of direct exposure.

“What this could suggest, and my lab is working on this a bit now, is perhaps if we could map cross reactivity for things like a peanut, you could become tolerant to peanut by eating something that has those shared proteins without actually having the peanut exposure,” Blum said.

References

1. Blum JE, Kong R, Schulman EA, et al. Identification and characterization of dietary antigens in oral tolerance. Sci Immunol. 2026;11(117):eab4684. doi:10.1126/sciimmunol.aeb4684. https://www.science.org/doi/10.1126/sciimmunol.aeb4684

2. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813. doi:10.1056/NEJMoa1414850. https://www.nejm.org/doi/full/10.1056/NEJMoa1414850