Tolerogenic Dendritic Cells in Gut Prevent Allergic Reactions to Food

To protect us from harmful invaders like viruses, the immune system must strike a careful balance—responding rapidly to threats while ignoring harmless substances such as food. While it's known that immune cells typically "tolerate" the body's own tissues and benign environmental inputs like dietary proteins, the exact mechanisms behind this selective response have remained unclear.

Now, researchers at NYU Langone Health have identified a specific type of immune cell in the gut that plays a crucial role in suppressing immune responses to food. These “tolerogenic dendritic cells” prevent unnecessary inflammation, allowing dietary proteins to pass through the digestive system without triggering an immune attack—unless the cells malfunction, in which case allergies may develop.

The Role of Prdm16 and RORγt

The study, published online April 14, 2025, in Nature, reveals that these tolerogenic dendritic cells rely on two key proteins—PR domain-containing 16 (Prdm16) and Retinoic Acid–Related Orphan Receptor-gamma-t (RORγt)—to protect against inappropriate immune activation. When the cells don’t function properly, mice were more prone to develop food allergies and asthma.

The findings build on the team’s earlier research, which showed these same cells also promote immune tolerance to beneficial gut bacteria—microorganisms essential for digestion and overall health. Until now, their role in food antigen tolerance was not fully understood.

“Our study shows that RORγt-expressing dendritic cells are key components in the immune regulatory response that prevents food allergies,”

Dan L. Littman, MD, PhD, senior author and professor at NYU Grossman School of Medicine

Dr. Littman, also a Howard Hughes Medical Institute Investigator, added that these findings support previous work linking the same cells to regulation of the body’s microbiome and potential protection from autoimmune diseases like Crohn’s.

How the Cells Work

The researchers confirmed the identity of these cells as a form of dendritic cell by analyzing the genes and proteins they express. Dendritic cells typically function by presenting small fragments of proteins—antigens—to T cells, which then “learn” to recognize and respond to those antigens in the future.

In this case, however, when tolerogenic dendritic cells present food or microbiome-related antigens, they guide T cells to become regulatory T cells—immune cells that actively suppress inflammation. This shift ensures that the immune system doesn’t overreact when it encounters the same harmless substances again.

The study found that mice lacking tolerogenic dendritic cells had significantly fewer regulatory T cells, leaving them more vulnerable to inflammation caused by food and microbial antigens. When exposed to these triggers, the mice developed excessive inflammatory responses, mimicking allergic reactions.

Implications for Human Health

In another important development, the researchers identified human counterparts of these tolerogenic dendritic cells by analyzing public gene sequencing data and human intestinal tissue samples. While it remains unclear how widespread these cells are in humans or whether they function similarly in all contexts, their clear identification in this study lays the groundwork for future investigations.

“If further experiments prove successful, our findings could lead to innovative ways to treat food allergies,” said Dr. Littman.
“For example, if someone has a peanut allergy, perhaps we can use tolerogenic dendritic cells to help create more regulatory T cells to suppress an allergic response.”

Looking ahead, the team aims to understand better where these dendritic cells originate in the body, how they develop, and which signals they rely on to carry out their immune-regulating functions.