RORyt extra-thymic aire expressing cells mediate oral tolerance and treg induction 2571

Abstract Description The immune system must distinguish pathogens from innocuous dietary antigens, but the precise mechanisms and cellular actors involved are unclear. Here, we demonstrate that RORyt-lineage antigen-presenting cells (APCs) expressing the Autoimmune Regulator (Aire) gene – referred to as RORyt extrathymic Aire expressing cells (RORyt eTACs) – are required for oral tolerance. Using lineage tracing and single-cell sequencing, we show that RORyt eTACs are of a myeloid-derived lineage and establish consensus identities for all RORyt-lineage APCs. We found that RORyt eTACs, but not type 3 innate lymphoid cells, are necessary and sufficient for oral tolerance induction. Upon depletion of RORyt eTACs, mice fail to develop food-specific Tregs and display severe delayed-type hypersensitivity responses. These findings establish RORyt eTACs as critical mediators of oral tolerance and suggest novel targets to modulate immune tolerance. Funding Sources NIH R01 AI145858, NIH 5T32AI007334, NIH 1F31AI172348, NIH 1F31CA288017, NIH 5T32GM141323, Pew Biomedical Scholars Program, Parker Institute for Cancer Immunotherapy, W.M. Keck Foundation Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)