2025-07-04
Unsung conductors of food tolerance
Allergology and Immunology Gastroenterology and Hepatology
#OralTolerance
#pTreg #IntestinalInflammation #LymphoidDCs #FoodAllergy
Immune tolerance to food is a cornerstone of gut health. It notably relies on peripheral regulatory T cells (pTreg), which prevent inappropriate reactions to food proteins. But who educates these cells? A U.S. research team has highlighted the crucial role of a rare subtype of dendritic cells expressing RORγt. Their absence may well explain certain forms of food allergy.
The study published in Cell shows that these cells, derived from the lymphoid lineage, are the true conductors of oral tolerance—far more than type 3 innate lymphoid cells (ILC3), previously suspected.
To solve this mystery, researchers created a mouse model (Rorc^E+7kbΔ/Δ) in which a cis-regulatory element located +7 kb from the Rorc gene was deleted. This site controls the expression of RORγt in certain immune cells. The deletion selectively eliminated ILC3s and RORγt⁺ dendritic cells, without affecting RORγt⁺ T cells.
Mutant mice exhibited a significant reduction in pTreg and an abnormal expansion of Th2 cells, indicating an immune imbalance typical of allergic responses. Notably, mice lacking only ILC3s maintained normal pTreg levels, confirming the unique role of RORγt⁺ dendritic cells.
Bone marrow transplants confirmed that the pTreg decrease stems from the absence of extrinsic signals provided by RORγt⁺ DCs, not from an intrinsic defect in T cells. In mutant recipients, pTregs dropped to 1.6% of CD4⁺ T cells (vs. 5.3% in controls), with a concurrent rise in Th2 cells.
When exposed to oral ovalbumin, Rorc^E+7kbΔ/Δ mice failed to induce pTreg FOXP3⁺ RORγt⁺ (<1%, vs. 5% in controls). Th2 cells reached 30% of OT-II cells (vs. 10%), accompanied by intestinal inflammation: increased permeability (FITC-dextran x2–3), elevated fecal lipocalin, and a doubling of goblet cells. In an asthma model, pulmonary Th2 cells exceeded 25%, with elevated anti-OVA IgE. Remarkably, this Th2 skewing persisted even in germ-free mice, underlining the importance of RORγt⁺ DCs.
In mice infected with Heligmosomoides polygyrus, the absence of RORγt⁺ DCs enhanced antiparasitic responses: fewer eggs by day 15 (200 vs. 600/g feces), more granulomas (6 vs. 2 on day 9), increased Th2 levels, and exaggerated mucus production. A stronger defense, but at the cost of immune imbalance.
Using a reporter mouse and single-cell RNA sequencing (scRNA-seq), researchers identified these CCR6⁺ RORγt⁺ migratory DCs enriched in cecum-draining lymph nodes (up to 2.5% of DCs). In 15-day-old pups, they represented 10% of migratory DC2s. In the absence of the +7 kb site, some subtypes (DCs II–IV) dropped by 70%, except for Janus cells expressing AIRE.
Lineage tracing revealed that over 70% of RORγt⁺ DCs originate from IL-7R⁺ lymphoid progenitors (vs. <10% for myeloid ones). In culture, these progenitors produced RORγt⁺ DCs in 4–6 days, especially when exposed to FLT3L, IL-7, and SCF.
RORγt⁺ dendritic cells emerge as major sentinels of gut immunity. Essential for inducing peripheral regulatory T cells (pTreg), they ensure tolerance to dietary antigens and prevent Th2-type immune deviations. Their absence triggers exaggerated inflammatory responses typical of allergic disorders. The precise identification of this population—particularly through markers like CCR6, Pigr, Tlr12, and Nr4a3—opens new avenues for their characterization in clinical settings such as food allergies and chronic inflammatory bowel diseases. These findings reposition RORγt⁺ DCs at the heart of oral tolerance mechanisms and suggest promising new therapeutic targets.
Immune tolerance to food is a cornerstone of gut health. It notably relies on peripheral regulatory T cells (pTreg), which prevent inappropriate reactions to food proteins. But who educates these cells? A U.S. research team has highlighted the crucial role of a rare subtype of dendritic cells expressing RORγt. Their absence may well explain certain forms of food allergy.
The study published in Cell shows that these cells, derived from the lymphoid lineage, are the true conductors of oral tolerance—far more than type 3 innate lymphoid cells (ILC3), previously suspected.
RORγt⁺ DCs: more than mere extras
To solve this mystery, researchers created a mouse model (Rorc^E+7kbΔ/Δ) in which a cis-regulatory element located +7 kb from the Rorc gene was deleted. This site controls the expression of RORγt in certain immune cells. The deletion selectively eliminated ILC3s and RORγt⁺ dendritic cells, without affecting RORγt⁺ T cells.
Mutant mice exhibited a significant reduction in pTreg and an abnormal expansion of Th2 cells, indicating an immune imbalance typical of allergic responses. Notably, mice lacking only ILC3s maintained normal pTreg levels, confirming the unique role of RORγt⁺ dendritic cells.
A key role in the immune environment
Bone marrow transplants confirmed that the pTreg decrease stems from the absence of extrinsic signals provided by RORγt⁺ DCs, not from an intrinsic defect in T cells. In mutant recipients, pTregs dropped to 1.6% of CD4⁺ T cells (vs. 5.3% in controls), with a concurrent rise in Th2 cells.
Lost tolerance, heightened inflammation
When exposed to oral ovalbumin, Rorc^E+7kbΔ/Δ mice failed to induce pTreg FOXP3⁺ RORγt⁺ (<1%, vs. 5% in controls). Th2 cells reached 30% of OT-II cells (vs. 10%), accompanied by intestinal inflammation: increased permeability (FITC-dextran x2–3), elevated fecal lipocalin, and a doubling of goblet cells. In an asthma model, pulmonary Th2 cells exceeded 25%, with elevated anti-OVA IgE. Remarkably, this Th2 skewing persisted even in germ-free mice, underlining the importance of RORγt⁺ DCs.
An advantage against parasites?
In mice infected with Heligmosomoides polygyrus, the absence of RORγt⁺ DCs enhanced antiparasitic responses: fewer eggs by day 15 (200 vs. 600/g feces), more granulomas (6 vs. 2 on day 9), increased Th2 levels, and exaggerated mucus production. A stronger defense, but at the cost of immune imbalance.
A rare but strategic subtype identified
Using a reporter mouse and single-cell RNA sequencing (scRNA-seq), researchers identified these CCR6⁺ RORγt⁺ migratory DCs enriched in cecum-draining lymph nodes (up to 2.5% of DCs). In 15-day-old pups, they represented 10% of migratory DC2s. In the absence of the +7 kb site, some subtypes (DCs II–IV) dropped by 70%, except for Janus cells expressing AIRE.
Confirmed lymphoid origin
Lineage tracing revealed that over 70% of RORγt⁺ DCs originate from IL-7R⁺ lymphoid progenitors (vs. <10% for myeloid ones). In culture, these progenitors produced RORγt⁺ DCs in 4–6 days, especially when exposed to FLT3L, IL-7, and SCF.
RORγt⁺ DCs: the missing link in food tolerance
RORγt⁺ dendritic cells emerge as major sentinels of gut immunity. Essential for inducing peripheral regulatory T cells (pTreg), they ensure tolerance to dietary antigens and prevent Th2-type immune deviations. Their absence triggers exaggerated inflammatory responses typical of allergic disorders. The precise identification of this population—particularly through markers like CCR6, Pigr, Tlr12, and Nr4a3—opens new avenues for their characterization in clinical settings such as food allergies and chronic inflammatory bowel diseases. These findings reposition RORγt⁺ DCs at the heart of oral tolerance mechanisms and suggest promising new therapeutic targets.
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