An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development

Area of Science:

• Immunology
• Developmental Biology
• Cell Biology

Background:

• Classical type 1 dendritic cells (cDC1s) are crucial for effective antiviral and antitumor immune responses.
• cDC1 development involves distinct transcriptional regulation, including the use of specific Irf8 enhancers at different stages.

Purpose of the Study:

• To elucidate the molecular mechanisms governing the developmental switch in cDC1 progenitors.
• To understand the role of transcription factors Nfil3, Id2, and Zeb2 in cDC1 lineage commitment.

Main Methods:

• Single-cell RNA sequencing of common dendritic cell progenitors (CDPs).
• Genetic epistasis experiments to determine the hierarchical relationships of key transcription factors.

Main Results:

• Identified a CDP subpopulation expressing Nfil3, Id2, and Zeb2, critical for cDC1 development.
• Demonstrated that Nfil3 is essential for the transition from a Zeb2^hi/Id2^lo to a Zeb2^lo/Id2^hi progenitor state.
• Showed this genetic circuit inhibits E-protein activity, preventing plasmacytoid dendritic cell differentiation and explaining the shift in Irf8 enhancer usage.

Conclusions:

• Nfil3 acts as a key regulator in the cDC1 developmental pathway, directing progenitor fate.
• The identified genetic circuit ensures lineage fidelity by blocking alternative cell fates and coordinating enhancer activity.