Essential Immune Cells in Intestine Cause Gut Inflammation, Allergic Responses to Foods When Absent

Researchers have identified that essential immune cells within the intestines prevent unwarranted attacks against harmless food allergens. These findings were published in Cell and demonstrated that in mouse models, the absence of these cells caused the subjects to experience gut inflammation and an allergic response to the food.¹

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The intestinal immune system can recognize friend from foe, tolerating many foods while destroying disease-causing invaders, explained the investigators. For about 30 million US individuals with food allergies—of whom about 4 million are children—immune cells can mistakenly identify food as a threat, triggering potentially life-threatening reactions. The most common food allergens include peanuts and tree nuts, shellfish, milk, eggs, and others.²

Specifically, the intestinal immune system maintains tolerance to harmless food proteins and gut microbiota through peripherally derived RORγt⁺ Tregs (pTregs), which prevent food intolerance and inflammatory bowel disease, according to the authors. They explained that studies indicated that RORγt⁺ antigen-presenting cells (APCs), which encompass rare dendritic cell (DC) subsets and type 3 innate lymphoid cells (ILC3s), may be the key to pTreg induction. In their study, they developed a mouse with reduced RORγt⁺ APCs by deleting a specific cis-regulatory element of Rorc encoding RORγt to investigate the role of RORγt⁺ APCs in pTreg induction in response to an oral antigen-mimicking food antigen.¹

During their investigation, the researchers treated the mice with ovalbumin—a highly allergenic protein found in egg whites—orally, then intranasally. The mice that lacked gut RORγt+ dendritic cells demonstrated signs of allergic lung inflammation, whereas subjects with these cells did not. Additionally, an analysis of the gut immune cells determined there was a present imbalance among the T cells that trigger immune responses to food particles—rather than those that dampen them—in the allergic mice, with a skewing toward the former.^1,2

“We are seeing a rapid global increase in food allergies that significantly impact quality of life,” Marco Colonna, MD, the Robert Rock Belliveau, MD, professor of pathology at WashU Medicine, said in a news release. “The lack of therapeutics to prevent and manage food allergies complicates the growing public health issue. Now that we know the players that establish tolerance to food allergens, we can devise innovative strategies to target them therapeutically and potentially prevent or treat food allergies.”²

Further, lineage tracing revealed that RORγt⁺ DCs share a lymphoid origin with ILC3s, which is consistent with their similar phenotypic traits. These findings highlight the role of lymphoid RORγt⁺ DCs in maintaining intestinal immune balance and preventing conditions like food allergies, according to the investigators.¹

“By removing RORγt⁺ dendritic cells from the gut in mice, we broke tolerance to food allergens,” co-first study author Patrick Rodrigues, PhD, a postdoctoral scholar, said in the news release. “The discovery is now inspiring us to see if we can do the opposite: prevent food allergies by supporting the activity of this cell population. Because RORγt⁺ dendritic cells are found in people, our finding presents an exciting new possibility to manage food allergies and other gut-related immune diseases such as celiac disease or inflammatory bowel disease.”²

The authors noted that, although the findings highlight RORγt⁺ DCs as key in pTreg induction and dietary antigen tolerance, the mechanisms that drive Th2 dysregulation and inflammation are still not clear. For this reason, future studies are required to further explore dietary antigen exposure, the spatial-temporal dynamics of RORγt⁺ DCs, as well as their interactions with food allergens. Regarding the lymphoid origin of RORγt⁺ DCs, further validation performed with in vivo transfer experiments will also be needed; however, these studies are considered to be challenging because of the “scarcity of precursors,” wrote the authors.¹

“Targeting the activity of RORγt⁺ dendritic cells has the potential to work even further upstream to prevent an immune response from first being triggered,” explained co-first study author Shitong Wu, MD/PhD student in Colonna’s lab, in the news release. “If that proves to be true, a therapy supporting the activity of this small population of cells might offer lasting tolerance to food allergens.”²

REFERENCES

1. Rodrigues PF, Wu S, Trsan T, et al. Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens. Cell. 2025. doi:10.1016/j.cell.2025.03.020

2. WashU Medicine. Researchers find intestinal immune cell prevents food allergies. News release. April 3, 2025. Accessed April 15, 2025. https://medicine.washu.edu/news/researchers-find-intestinal-immune-cell-prevents-food-allergies/