Terminal differentiation of dendritic cells

Dendritic cells (DCs) are essential for the initiation of an effective immune response. Despite this, our understanding of the molecular regulation of this important cell type has lagged significantly behind that of other lymphoid populations such as B and T cells, but recent development of various tools has greatly facilitated progress in the field. Here, we review the transcription factors that drive peripheral DC subset fate decisions. While Pu.1, Ikaros, and Gfi-1 are essential for precursor DCs to give rise to monocytes, conventional DCs, and plasmacytoid DCs, the balance between E2-2 and Id2 directs committed precursors along a pDC or cDC lineage, respectively. Several transcription factors such as Batf3, Nfil3, and Id2 are required for different DC subsets at steady-state and drive segregation into the individual DCs subsets late in development in the CD8 lineage. During inflammation, CD8-expressing DCs emerge that feature many of the hallmarks of classical CD8α(+) DCs but surprisingly do not depend on the same transcription factors. Thus, the immune system has developed two pathways of DC differentiation that enable it to maintain homeostatic balance and to respond rapidly to the emergency requirement for DCs that might occur during infection.