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.

miR-22 Controls Irf8 mRNA Abundance and Murine Dendritic Cell Development

“…1B). To examine whether miR-22 is regulated during DC development, we cultured lin − Flt3 + DC progenitors ex vivo with Flt3L or GM-CSF, conditions that promote, respectively, the differentiation of pDCs and cDCs in an approximate 1:1 ratio, or selective cDC differentiation including CD11c + CD11b + B220 − cDCs (reviewed in [25]). We found that miR-22 was highly induced in GM-CSF cultures, while slightly repressed in Flt3L cultures (Fig.…”

“…cDCs have been further subdivided on the basis of tissue localization, cell surface marker protein expression and function. Both cDC and pDC populations arise from common DC progenitors (CDPs, lin − Flt3 + CD115 + CD117 −/lo ) in bone marrow, under control of key cytokines and lineage-restricted transcription factors (reviewed in [24] and [25]). Despite accumulating evidence indicating the important roles of miRNAs in hematopoiesis, little is known about their function in controlling DC development.…”

Innate immune regulation by STAT‐mediated transcriptional mechanisms

“…). These results suggest a model in which GM‐CSF‐responsive STAT5 and Flt3L‐responsive STAT3 signaling in CDPs influences the expression of the key DC transcriptional regulators Id2 and E2‐2 ( Fig. ).…”

The role of the vascular dendritic cell network in atherosclerosis

“…pDCs derive directly from common dendritic precursor cells in the bone marrow in a Flt3L-dependent manner and then travel to lymphoid and nonlymphoid tissues via the blood, rather than entering peripheral tissues as a precursor cell (126,158,231). Development of pDCs has been shown to depend on the transcription factors E2-2 (Tcf4) (40,72) and IRF8 (200,226), among others (122). Comparative microarray studies show that pDCs exhibit similar gene expression profile regardless of their tissue of origin, suggesting that pDCs comprise a single DC subset of common developmental origin (150).…”