AireDTR Single Cell
The immune system must distinguish pathogens from innocuous dietary antigens, but the precise mechanisms and cellular actors involved are unclear. Here, we demonstrate that ROR?t-lineage antigen-presenting cells (APCs) expressing the Autoimmune Regulator (Aire) gene – referred to as ROR?t eTACs – are required for oral tolerance. Using lineage tracing and single-cell sequencing, we show that ROR?t eTACs are of a myeloid-derived lineage and establish consensus identities for all ROR?t-lineage APCs. We found that ROR?t eTACs, but not type 3 innate lymphoid cells, are necessary and sufficient for oral tolerance induction. Upon depletion of ROR?t eTACs, mice fail to develop food-specific Tregs and display severe delayed-type hypersensitivity responses. These findings establish ROR?t eTACs as critical mediators of oral tolerance and suggest novel targets to modulate immune tolerance. Overall design: We obtained lymph nodes (mesenteric,cervical, inguinal, axillary, brachial, and para-aortic) from AireDTR mice and FACS-sorted tdTmt+ MHCII+ cells for subsequent scRNA-seq.