Continuous Expression of the Transcription Factor E2-2 Maintains the Cell Fate of Mature Plasmacytoid Dendritic Cells

The interferon-producing plasmacytoid dendritic cells (pDCs) share common progenitors with antigen-presenting classical dendritic cells (cDCs), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of pDCs is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral pDCs caused their spontaneous differentiation into cells with cDC properties. This included the loss of pDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology, and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key pDC-specific and lymphoid genes, as well as to certain genes enriched in cDCs. Thus, E2-2 actively maintains the cell fate of mature pDCs and opposes the “default” cDC fate, in part through direct regulation of lineage-specific gene expression programs. [Display omitted] ► Deletion of E2-2 from mature pDCs causes phenotypic conversion to cDC-like cells ► E2-2-deficient pDCs acquire the morphology and gene expression signature of cDCs ► E2-2 directly binds to multiple pDC-enriched target genes ► E2-2 maintains Bcl11a and represses Id2 expression in pDCs