#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.
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.
Read next: Peanut under control?
