RORγt dendritic cells are a distinct lymphoid-derived lineage.

Science immunology
Authors
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 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 +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 (T) 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 T cell-mediated immune homeostasis.

Year of Publication
2026
Journal
Science immunology
Pages
eaed7439
Date Published
01/2026
ISSN
2470-9468
DOI
10.1126/sciimmunol.aed7439
PubMed ID
41591258
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