Flexible fate commitment of E2-2high common DC progenitors implies tuning in tissue microenvironments

The basic helix-loop-helix transcription factor E2-2 is essential for the development of plasmacytoid dendritic cells (pDCs) but not conventional DCs (cDCs). Here, we generated E2-2 reporter mice and demonstrated that an E2-2(high) fraction among common DC progenitors, which are a major source of pDCs and cDCs in the steady state, strictly gave rise to pDCs in the presence of Flt3 (Fms-like tyrosine kinase receptor-3) ligand ex vivo or in the secondary lymphoid organs when transferred in vivo. However, in the small intestine, some of these E2-2(high) progenitors differentiated into cDCs that produced retinoic acid. This transdifferentiation was driven by signaling via the common beta receptor, a receptor for the cytokines IL-3, IL-5 and GM-CSF, which are abundant in the gut. In the presence of GM-CSF and Flt3 ligand, E2-2(high)-progenitor-derived cDCs consistently induced Foxp3(+) T-reg cells ex vivo. Our findings reveal the commitment and flexibility of E2-2(high) progenitor differentiation and imply that pertinent tuning machinery is present in the gut microenvironment.