Proteins Mediating Food Tolerance Identified

A new investigation published in Science Immunology uncovers how the immune system actively recognizes specific proteins in everyday foods like corn, soy, and wheat to establish oral tolerance. Unlike allergy research, which focuses on immune overreactions, this work examines why most people safely consume foods that harm others with allergies. The findings highlight regulatory T cells, or Tregs, that scan intestinal contents for key protein fragments called epitopes, signaling safety and preventing allergic responses.

According to senior author Elizabeth Sattely, “We know a lot about what the immune system sees and does if a patient has an allergy, but we know very little about what happens when things go right.” Previously, tolerance was viewed as the immune system simply ignoring food. The study demonstrates it involves active surveillance by Treg cells, which preferentially respond to certain epitopes rather than triggering inflammatory reactions.

The Stanford University team, which included co-first authors Jamie Blum and Ryan Kong, analyzed mouse chow containing corn, wheat, and soy—ingredients common in human diets. They pinpointed short chemical sequences within larger proteins that bias Tregs toward a calming response. “We found that the regulatory T cells are sort of biased towards some peptides more than others,” Sattely explained. “Not all of your food is being seen equally by the immune system. The T cells are looking for these specific proteins.”

In corn, Tregs targeted a single epitope from zein, a protein in the kernel's interior. Kong observed: “What really surprised me was how focused the mechanism is. In the case of corn, the Treg cells zero in on a single epitope that is part of a larger molecule, zein, a protein in the fleshy interior of the corn kernel.” This selectivity suggests the immune system learns tolerance from a narrow set of molecular signals.

Blum added that zein-specific T cell development depends on the protein's format in food and the gut microbial community. Although demonstrated in mice, the researchers anticipate mapping similar epitopes for humans. Sattely envisions a library of tolerance-biased epitopes to design treatments that activate regulatory T cells in allergy patients or create early exposures to prevent allergies in at-risk children.

The team plans to engineer plant proteins by removing or disabling key epitopes and test their effects on immune responses, starting in mice. Sattely concludes: “For now, we’ve learned that tolerance is defined as more than the mere absence of allergy. It is a specific, peptide-guided immune training program that we can someday harness to help people eat without fear.”