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

Area of Science:

• Immunology
• Developmental Biology
• Cell Biology

Background:

• The transcription factor E2-2 is crucial for plasmacytoid dendritic cell (pDC) development.
• Conventional dendritic cells (cDCs) and pDCs arise from common DC progenitors.
• The role of E2-2 in progenitor plasticity, particularly in specific microenvironments, remains incompletely understood.

Purpose of the Study:

• To investigate the differentiation potential of E2-2high common DC progenitors.
• To explore the influence of the gut microenvironment on progenitor cell fate.
• To determine the capacity of E2-2high progenitor-derived cDCs to induce regulatory T cells.

Main Methods:

• Generation of E2-2 reporter mice for tracking E2-2 expression.
• Ex vivo and in vivo differentiation assays of common DC progenitors.
• Cytokine signaling pathway analysis (common β receptor, IL-3, IL-5, GM-CSF, Flt3 ligand).
• Induction of regulatory T cells (Tregs) by differentiated cDCs.

Main Results:

• E2-2high progenitors exclusively generated pDCs in the presence of Flt3 ligand or in secondary lymphoid organs.
• In the small intestine, E2-2high progenitors differentiated into retinoic acid-producing cDCs, driven by common β receptor signaling.
• GM-CSF and Flt3 ligand stimulation of E2-2high progenitor-derived cDCs induced Foxp3+ Treg cells.

Conclusions:

• E2-2high progenitors exhibit both commitment to pDC lineage and flexibility for transdifferentiation into cDCs.
• The gut microenvironment possesses specific signaling cues, such as common β receptor agonists, that promote cDC differentiation from these progenitors.
• E2-2high progenitor-derived cDCs play a role in inducing immune tolerance via Treg cell induction within the gut.