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Il7rKO Single Cell

ABSTRACT: The immune system must distinguish pathogens from innocuous dietary antigens, but the precise mechanisms and cellular actors involved are unclear. Here, we demonstrate that RORγt-lineage antigen-presenting cells (APCs) expressing the Autoimmune Regulator (Aire) gene – referred to as RORγt eTACs – are required for oral tolerance. Using lineage tracing and single-cell sequencing, we show that RORγt eTACs are of a myeloid-derived lineage and establish consensus identities for all RORγt-lineage APCs. We found that RORγt eTACs, but not type 3 innate lymphoid cells, are necessary and sufficient for oral tolerance induction. Upon depletion of RORγt eTACs, mice fail to develop food-specific Tregs and display severe delayed-type hypersensitivity responses. These findings establish RORγt eTACs as critical mediators of oral tolerance and suggest novel targets to modulate immune tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE291696 | GEO | 2025/04/15

REPOSITORIES: GEO

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Project 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 RORγt-lineage antigen-presenting cells (APCs) expressing the Autoimmune Regulator (Aire) gene – referred to as RORγt eTACs – are required for oral tolerance. Using lineage tracing and single-cell sequencing, we show that RORγt eTACs are of a myeloid-derived lineage and establish consensus identities for all RORγt-lineage APCs. We found that RORγt eTACs, but not type 3 innate lymphoid cells, are necessary and sufficient for oral tolerance induction. Upon depletion of RORγt eTACs, mice fail to develop food-specific Tregs and display severe delayed-type hypersensitivity responses. These findings establish RORγt eTACs as critical mediators of oral tolerance and suggest novel targets to modulate immune tolerance.

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Project description:A key feature of immune tolerance is the ability to distinguish pathogens from innocuous signals including dietary antigens, but the precise mechanisms of oral tolerance induction and the key cellular actors have remained unclear. Classical dendritic cells (cDCs) have previously been implicated in the generation of regulatory T cells (Tregs) and T-cell anergy in response to food antigens in gut-associated lymphoid tissue1, but here we demonstrate that RORγt-lineage antigen-presenting cells (APCs), specifically RORγt-lineage cells expressing the Autoimmune Regulator (Aire) gene – referred to as RORγt eTACs – are the critical APC population required for oral tolerance induction. We reconcile the identity of these rare RORγt-lineage APC populations across new and all known single-cell transcriptomic datasets to establish consensus identities and show that RORγt eTACs2 are a unique myeloid-derived lineage distinct from innate lymphoid cells (ILCs) which are both necessary and sufficient for oral tolerance induction.

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