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

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.