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How the Immune System Actively Builds Tolerance to Food

In food allergies, the body’s defense system, called the immune system, reacts to harmless food as if it were a threat. To understand why this happens, scientists first need to know how the body develops a tolerance to a food.

A new study showed that certain parts of dietary proteins normally act as signals that foods are safe. Researchers found seven different sensors in specialized immune cells in the mouse gut, each reacting to specific proteins in mouse chow:

  1. Five sensors activated by a corn protein
  2. One sensor activated by a wheat protein
  3. One sensor activated by a soybean protein

These sensors only detected certain parts of the proteins, called epitopes. The most frequently recognized epitope was on a corn protein.

The specialized cells that recognized the corn protein first appeared when the mice were four weeks of age—about the same time that the mice first ate the food. These cells then sent signals to other immune cells not to attack the food protein.

“For a long time, we thought food tolerance simply meant the immune system was ignoring the foods we eat—that is to say that tolerance is the absence of allergy,” says Dr. Elizabeth Sattely of Stanford University, co-leader of the study. “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 found, the cells signal the immune system that the food is safe.”

Study Details

Reference: Identification and characterization of dietary antigens in oral tolerance. Blum JE, Kong R, Schulman EA, Chen FM, Upadhyay R, Romero-Meza G, Littman DR, Fischbach MA, Nagashima K, Sattely ES. Sci Immunol. 2026 Mar 6;11(117):eaeb4684. doi:10.1126/sciimmunol.aeb4684. PMID:41790933.

Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute (NCI); National Science Foundation; Howard Hughes Medical Institute; Life Sciences Research Foundation; Rosenfield and Glassman Foundation; Ono Pharma Foundation; Stanford Bio-X; Laura and Isaac Perlmutter Cancer Center.

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