RORγt⁺ dendritic cells are a distinct lymphoid-derived lineage

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Establishing immune tolerance to commensals and food antigens is vital.
• The precise mechanisms governing tolerogenic dendritic cell (DC) lineage development remain incompletely understood.

Purpose of the Study:

• To identify and characterize the lineage and developmental requirements of RORγt+ DCs in mice.
• To elucidate the molecular regulators essential for RORγt+ DC development and function in maintaining immune homeostasis.

Main Methods:

• Lineage tracing and single-cell transcriptomics in mice.
• Analysis of gene regulatory elements (enhancers) and transcription factors (PRDM16, PU.1, REV-ERBα/β).
• Assessment of RORγt+ DC differentiation, regulatory T cell induction, and immune responses upon genetic manipulation.

Main Results:

• RORγt+ DCs represent a distinct lymphoid-derived lineage originating from bone marrow progenitors.
• The RORγt+ DC lineage development is critically dependent on the 'Rorc +7 kb' enhancer and transcription factors PRDM16 and PU.1.
• Loss of key regulators impairs RORγt+ DC differentiation, reduces regulatory T cell induction, and promotes T helper 2 cell responses.

Conclusions:

• Murine RORγt+ DCs are a lymphoid-derived lineage essential for peripheral immune homeostasis.
• Enhancer and transcription factor regulation of RORγt+ DC development is critical for inducing regulatory T cells and maintaining tolerance.