Abstract
Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFβ function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFβ activation, suggesting that Ikaros is an upstream negative regulator of the TGFβ pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with γ-secretase inhibitors, which affects both TGFβ-dependent and -independent pathways, but is Notch-independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity.
Highlights
Dendritic cells (DCs) are essential modulators of the immune response [1]
Dendritic cells (DCs) are an important component of the immune system, and exist as two major subtypes: conventional DCs which present antigen via major histocompatibility class II molecules, and plasmacytoid DCs which act mainly as producers of type-I interferon in response to viral infections. Both types of DCs derive from a common dendritic progenitor (CDP), but the genetic pathways that influence their development are not completely understood
They can be broadly divided into conventional DCs, which are required for antigen presentation, and plasmacytoid DCs, which secrete high quantities of type-I interferon (IFN-α, -β, -ω) upon certain viral infections [2, 3]. cDCs are further divided into cDC1 (CD8+) and cDC2 (CD11b+) subsets
Summary
Dendritic cells (DCs) are essential modulators of the immune response [1]. They can be broadly divided into conventional DCs (cDC), which are required for antigen presentation, and plasmacytoid DCs (pDC), which secrete high quantities of type-I interferon (IFN-α, -β, -ω) upon certain viral infections [2, 3]. cDCs are further divided into cDC1 (CD8+) and cDC2 (CD11b+) subsets. Dendritic cells (DCs) are essential modulators of the immune response [1] They can be broadly divided into conventional DCs (cDC), which are required for antigen presentation, and plasmacytoid DCs (pDC), which secrete high quantities of type-I interferon (IFN-α, -β, -ω) upon certain viral infections [2, 3]. CDCs are further divided into cDC1 (CD8+) and cDC2 (CD11b+) subsets. Both DC lineages develop in the bone marrow. The relationships and interactions between these players remain unclear, and this is important to understand if we wish to manipulate DC function
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