Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens
Patrick Fernandes Rodrigues, Shitong Wu, Tihana Tršan, Santosh K. Panda, José Luís Fachi, Yizhou Liu, Siling Du, Sarah de Oliveira, Alina Ulezko Antonova, Darya Khantakova, Raki Sudan, Pritesh Desai, Michael S. Diamond, Susan Gilfillan, Stephen K. Anderson, Marina Cella, Marco Colonna
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 pTreg 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 an increase in T helper (Th)2 cells. Conversely, ILC3-deficient mice showed no pTregs or Th2 cell abnormalities. Lineage tracing revealed that RORγt + DCs share a lymphoid origin with ILC3s, consistent with their similar phenotypic traits. These findings highlight the role of lymphoid RORγt + DCs in maintaining intestinal immune balance and preventing conditions like food allergies.