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RORγt⁺ Dendritic Cells Are a Distinct Lymphoid-Derived Lineage

ABSTRACT: How tolerogenic dendritic cell (DC) lineages are established to prevent inappropriate immune responses to commensals and food antigens remains unclear. We identify RORγt⁺ DCs in mice as a distinct lymphoid-derived lineage to safeguard intestinal tolerance. Using lineage tracing and single-cell transcriptomics, we unveiled bone marrow–resident Rorc(t)⁺ progenitors, which include a RORγt⁺ innate lymphoid progenitor (RILP) that generates both ILC3s and RORγt⁺ DCs, and a pre-RORγt⁺ DC precursor committed exclusively to the RORγt⁺ DC lineage. RORγt⁺ DC development required the Rorc +7 kb enhancer, whose accessibility was ensured by the repressors REV-ERBα and REV-ERBβ, and depended on the transcription factors PRDM16 and PU.1 for lineage commitment. Loss of any of these regulators abrogated RORγt⁺ DC differentiation, reduced peripheral regulatory T (Treg) cell induction, and skewed toward T helper 2 responses. Together, these findings define murine RORγt⁺ DCs as a lymphoid-derived lineage whose enhancer- and transcription factor–driven development is essential for peripheral Treg cell-mediated immune homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE312414 | GEO | 2026/01/26

REPOSITORIES: GEO

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			Action	DRS
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	GSE312414_barcodes.tsv.gz	Tabular
	GSE312414_features.tsv.gz	Tabular
	GSE312414_matrix.mtx.gz	Other
	GSE312414_scRNASeq_InVitro_HTO_information.xlsx	Xlsx

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Project description:How tolerogenic dendritic cell (DC) lineages are established to prevent inappropriate immune responses to commensals and food antigens remains unclear. We identify RORγt⁺ DCs in mice as a distinct lymphoid-derived lineage to safeguard intestinal tolerance. Using lineage tracing and single-cell transcriptomics, we unveiled bone marrow–resident Rorc(t)⁺ progenitors, which include a RORγt⁺ innate lymphoid progenitor (RILP) that generates both ILC3s and RORγt⁺ DCs, and a pre-RORγt⁺ DC precursor committed exclusively to the RORγt⁺ DC lineage. RORγt⁺ DC development required the Rorc +7 kb enhancer, whose accessibility was ensured by the repressors REV-ERBα and REV-ERBβ, and depended on the transcription factors PRDM16 and PU.1 for lineage commitment. Loss of any of these regulators abrogated RORγt⁺ DC differentiation, reduced peripheral regulatory T (Treg) cell induction, and skewed toward T helper 2 responses. Together, these findings define murine RORγt⁺ DCs as a lymphoid-derived lineage whose enhancer- and transcription factor–driven development is essential for peripheral Treg cell-mediated immune homeostasis.

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