A STATus report on DC development

Abstract

DCs have a vital role in the immune system by recognizing exogenous or self-antigens and eliciting appropriate stimulatory or tolerogenic adaptive immune responses. DCs also contribute to human autoimmune disease and, when depleted, to immunodeficiency. Moreover, DCs are being explored for potential use in clinical therapies including cancer treatment. Thus, understanding the molecular mechanisms that regulate DCs is crucial to improving treatments for human immune disease and cancer. DCs constitute a heterogeneous population including plasmacytoid (pDC) and classic (cDC) subsets; however, the majority of DCs residing in lymphoid organs and peripheral tissues in steady state share common progenitor populations, originating with hematopoietic stem cells. Like other hematopoietic lineages, DCs require extracellular factors including cytokines, as well as intrinsic transcription factors, to control lineage specification, commitment, and maturation. Here, we review recent findings on the roles for cytokines and cytokine-activated STAT transcription factors in DC subset development. We also discuss how cytokines and STATs intersect with lineage-regulatory transcription factors and how insight into the molecular basis of human disease has revealed transcriptional regulators of DCs. Whereas this is an emerging area with much work remaining, we anticipate that knowledge gained by delineating cytokine and transcription factor mechanisms will enable a better understanding of DC subset diversity, and the potential to manipulate these important immune cells for human benefit.

Figure 1.. Control of DC subset development by cytokines under steady state and inflammatory conditions.

The ability of cytokines to positively regulate specific DC lineages is indicated by →; negative effects are indicated by ⊢. ^aIFN-α-IFNAR signals were shown to control the accrual of pDCs in Peyer's patches [106]. ^b,cType I IFN suppresses the development of CD8α⁺ and CD8α⁻ DCs, whereas TGF-β inhibits CD11c⁺B220⁻ DC production [119, 141, 147, 155, 156]. ^dThe role of M-CSFR ligands (M-CSF or IL-34) was demonstrated in the development of CD103⁻CD11b⁺CX₃CR1⁺ DCs in lamina propria [117]. ^eMice that lack M-CSFR show a more severe deficiency in LCs than those lacking M-CSF [57]. ^fTGF-β drives development of LC-like cells in human monocyte cultures, in the presence of GM-CSF and IL-4 [52].

Figure 2.. Regulation of DC-related transcription factors by cytokine-responsive STATs.

Black arrows indicate pathways defined in DCs or DC progenitors; blue arrows indicate pathways identified elsewhere, yet require evaluation in DCs and their progenitors.