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

Abstract

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 (CDPs), which are a major source of pDCs and cDCs in the steady state, strictly gave rise to pDCs in the presence of Flt3 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 β 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⁺ regulatory T 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.