What Makes a pDC: Recent Advances in Understanding Plasmacytoid DC Development and Heterogeneity

Abstract

Dendritic cells (DCs) are professional antigen presenting cells (APCs) that originate in the bone marrow and are continuously replenished from hematopoietic progenitor cells. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) are distinguished by morphology and function, and can be easily discriminated by surface marker expression, both in mouse and man. Classification of DCs based on their ontology takes into account their origin as well as their requirements for transcription factor (TF) expression. cDCs and pDCs of myeloid origin differentiate from a common DC progenitor (CDP) through committed pre-DC stages. pDCs have also been shown to originate from a lymphoid progenitor derived IL-7R⁺ FLT3⁺ precursor population containing cells with pDC or B cell potential. Technological advancements in recent years have allowed unprecedented resolution in the analysis of cell states, down to the single cell level, providing valuable information on the commitment, and dynamics of differentiation of all DC subsets. However, the heterogeneity and functional diversification of pDCs still raises the question whether different ontogenies generate restricted pDC subsets, or fully differentiated pDCs retain plasticity in response to challenges. The emergence of novel techniques for the integration of high-resolution data in individual cells promises interesting discoveries regarding DC development and plasticity in the near future.

Keywords: DC progenitor; dendritic cell development; hematopoiesis; heterogeneity; plasmacytoid dendritic cells; plasticity.

Figure 1

Converging plasmacytoid dendritic cell differentiation pathways. Plasmacytoid dendritic cells (pDCs) can be derived from both myeloid and lymphoid progenitors. Common DC progenitors (CDPs) arise from lymphoid primed multipotent progenitors (LMPPs) either directly or via macrophage-DC progenitors (MDPs). CDPs contain precursor cells committed to conventional DC (cDC) and plasmacytoid DC fates, and M-CSFR⁻ CDPs have higher pDC potential than M-CSFR⁺ CDPs. A fraction of CDPs can give rise to CCR9^low pDC-like precursor cells and then CCR9^high pDCs in an E2-2 dependent manner. pDC-like cells retain the potential to differentiate into cDCs as well as CCR9^high mature pDCs. Inhibitor of DNA binding 2 (Id2), which inhibits E2-2 activity, needs to be suppressed to allow pDC differentiation. pDCs are also generated via the lymphoid pathway, from IL-7R⁺ lymphoid progenitors (LPs) which give rise to Ly-6D single positive (SP) LP and subsequently to Ly-6D Siglec-H double positive (DP) pre-pDC, terminally committed to the pDC fate.