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Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens

ABSTRACT: 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. Recent studies suggested that RORγt+ antigen-presenting cells (APCs), which encompass rare dendritic cell (DC) subsets and type 3 innate lymphoid cells (ILC3s), are key to pTregs induction. Here, we developed a mouse with reduced RORγt+APCs by deleting a specific cis-regulatory element of Rorc encoding RORγt. Single-cell RNA-sequencing and flow cytometry analyses confirmed the depletion of a RORγt+DC subset and ILC3s. These mice showed a secondary reduction in pTregs, impaired tolerance to oral antigens and increase in Th2 cells. Conversely, newly and previously generated ILC3-deficient mice showed no pTregs or Th2 cells abnormalities. Lineage tracing revealed that RORγt+DCs share a lymphoid origin with ILC3s, consistent with their similar phenotypic traits. These findings highlight a unique role of lymphoid RORγt+DCs in maintaining intestinal immune balance and preventing conditions like food allergies.

ORGANISM(S): Mus musculus

PROVIDER: GSE289268 | GEO | 2025/04/03

REPOSITORIES: GEO

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Project description:Gene expression profile of dendritic cells (DC) of mesenteric lymph node (mLN) and lamina propria of small intestine (SI-LP) of control mice and mice lacking RelB expression in DCs at steady state, four days and 14 days after infection with Heligmosomoides polygyrus bakeri (Hpb) Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Tregs). Specific DC subsets or DC-intrinsic pathways regulate immunity against pathogens but also tolerance to harmless antigens derived from food or microbiota at barrier sites, but underlying mechanisms in the intestinal tract remain poorly defined. Here, we provide evidence that the alternative NF-B family member RelB controls a defined transcriptional program in migratory DC subsets of mesenteric lymph nodes and the small intestinal lamina propria. Functionally, ablation of RelB in dendritic cells result in increased Foxp3+ Treg cell numbers but decreased RORt peripheral Treg cell numbers maintained even under inflammatory conditions. Single-cell RNA-sequencing revealed a complete RelB dependency for the differentiation of cryptopatches and isolated lymphoid follicles-associated DCs (CIA-DCs) in the lamina propria of the small intestine. In addition, we show a RelB-dependent signature of migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction by affecting the expression of chemokines (Ccl22, Ccl17), migration behavior (Cd63), co-stimulatory molecule (Cd80, Cd40, Cd200, Tnfsf4), and tolerance-related integrin (Itgb5, Itgb8) expression. Functionally, increased Treg cell numbers in DC-specific RelB knockout animals did not show any risk of increased reactions in a model of food allergy but instead prevented protective Th2 immune responses in the intestines after infection with Heligmosomoides polygyrus bakeri despite their slight steady-state type 2 immune bias. This protection was dependent on elevated Treg cell frequencies during primary infection as a result of bystander immune tolerance. Thus, RelB expression in conventional DCs acts as a rheostat to establish a tolerogenic set point that is maintained even during infection and strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.

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Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens

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