Scientists uncover how the immune system actively builds food tolerance

Food allergies are serious and, for some, potentially deadly. And yet, despite decades of research into allergies and what causes them, very little is known about why the vast majority of people are able to tolerate foods that can sicken or even kill others.

"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," said Elizabeth "Beth" Sattely, an associate professor of chemical engineering in the School of Engineering at Stanford University and senior author of a new study tackling this question in the journal Science Immunology.

Sattely and her co-authors revealed that oral tolerance – an active function of the immune system – involves recognition of specific proteins in common food sources like corn, soy, and wheat that signal to the immune system that they are safe to eat. The findings open new therapeutic avenues for preempting or undoing dangerous food allergies.

Active investigation

For a long time, we thought food tolerance simply meant the immune system ignoring the foods we eat – that is to say that tolerance is the absence of allergy. But we now know that tolerance is active and adaptive behavior. Certain cells in our intestines survey the foods we eat, looking for specific proteins. When they find them, the cells signal the immune system that the food is safe."

Elizabeth "Beth" Sattely, associate professor of chemical engineering, School of Engineering, Stanford University

The searchers are known as regulatory T cells – or Tregs. They are the immune system's peacekeepers, scanning food for these key proteins and calming the immune system when they find them, preventing an allergic overreaction to an otherwise safe food.

Sattely and team, including co-first authors Jamie Blum, a former postdoctoral scholar in Sattely's lab, and Ryan Kong, a Stanford graduate student in chemical engineering, closed the gap in understanding by identifying specific fragments of dietary proteins – short chemical sequences known as epitopes – that are presented to Treg cells in the intestines and preferentially stimulate a soothing regulatory response, rather than an inflammatory T cells that produce allergies.

While the researchers stress that they have currently demonstrated the work in lab mice, they believe they can map these and similar molecular inputs that could lead to oral tolerance in humans.

Teaching tolerance

Blum, Kong, and co-author Kazuki Nagashima conducted experiments and analyses that enabled the team to pinpoint these tolerance-linked epitopes within complex diets, examining mice chow for ingredients that overlap with human diets – corn, wheat, and soy specifically. They believe tolerance hinges on a few standout epitopes – those shorter sections of larger proteins – that cue the regulatory 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."

This finding implies that the immune system learns oral tolerance from a limited set of molecular cues. The researchers can foresee building a library of tolerance-biased epitopes that could be used to design interventions that steer the immune system toward tolerance instead of allergy.

"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," Kong noted. "Considering the enormous number of potential intestinal antigens, it was striking to see such a targeted response."

Understanding why the immune system selects this particular peptide, and not others, could teach us more about how the body naturally develops tolerance to food, Kong added. This knowledge, in turn, could be used to help reprogram the immune system to prevent or even treat food allergies.

Future foods

"One of the most exciting findings is that the development of the zein-specific T cells depends on the format of the protein in the food and the intestinal microbial community," explained Blum, who now leads her own lab at The Salk Institute for Biological Studies. "We are now working to determine the exact biological mechanisms involved."

Potential research avenues could lead in several directions. Sattely can foresee compiling a molecular map of tolerance-biased epitopes to guide treatment and therapeutic strategies that reduce food allergies. In this guise, the tolerance-favoring peptides might serve as precision tools that can induce calming regulatory T cells into action for patients with existing food allergies. She can also imagine the possibility of a preventative tolerance "vaccine" for those at high risk.

"We might be able to treat a patient who currently has a food allergy and induce these regulatory T cells that would allow them to overcome their allergy," she said. "Or, we could design early-stage, childhood exposures that would guide allergy-prone patients toward tolerance, before allergies develop."

Sattely's research background is studying plant chemistry and its effects on human health. She says her future research will dig deeper into the chemistry and engineering of food proteins – especially seed proteins that form a large portion of human protein sources – and test how fine-tuning them affects immune outcomes. Along that trajectory, the team plans to explore specific plant proteins and synthesize versions with the key epitopes disabled or removed to test immune responses, first in mice and, eventually, in humans.

"For now, we've learned that tolerance is defined as more than the mere absence of allergy," Sattely summed up. "It is a specific, peptide-guided immune training program that we can someday harness to help people eat without fear."