Ikaros cooperates with Notch activation and antagonizes TGFβ signaling to promote pDC development

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.

Transcriptional Networks Driving Dendritic Cell Differentiation and Function

“…Surprisingly, despite their similarities, to date, there is very little evidence of genetic interactions between the regulators of cDC1 and cDC2. ll 944 Immunity 52, June 16, 2020 Review to repress CDP development in a Notch-dependent manner (Mastio et al, 2018).…”

“…Mice homozygous for a strongly hypomorphic allele of Ikzf1 have a block in development in the bone marrow, resulting in few peripheral pDCs (Allman et al, 2006). IKAROS promotes pDC formation by antagonizing transforming growth factor b (TGF-b) signaling that is known to promote cDC formation (Mastio et al, 2018). Within the steady-state hematopoietic system, Runx2 is expressed only in pDCs where it is a target gene of E2-2 (activated) (Sawai et al, 2013) and PU.1 (repressed) (Chopin et al, 2019).…”

“…This suggests that one of the key functions of the high PU.1 concentration in developing cDCs is to silence the pDC program. In contrast, one function of IKAROS in CDPs and pDCs is to prevent the premature expression of cDC genes (Mastio et al, 2018).…”

Specific Targeting of Notch Ligand-Receptor Interactions to Modulate Immune Responses: A Review of Clinical and Preclinical Findings

“…This is associated with an upregulation in of Ikaros and IRF8 signaling which shunts the developing pre-T cell toward differentiating into dendritic cells. A network of interactions between Notch, Wnt, Ikaros, and IL10 (among several others) is involved in determining the balance between T and myeloid lineage commitment under normal physiologic conditions (105)(106)(107)(108). Given the indispensable role of Notch in ensuring normal thymic T cell development, therapeutic interventions to restore Notch activity in thymic and peripheral T cells can promote antitumor immunity (109,110).…”

Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

“…Development of pDCs begins in the bone marrow, where these cells originate from a common dendritic cell (DC) progenitor and culminates with migration and maturation in the blood and tissue [2,8]. The fate of the DC progenitor is dependent on the balance of key developmental factors, including ID2, IKZF1, NOTCH1, SPIB, and TCF4 [9][10][11][12][13]. In humans, myeloid dendritic cells (mDCs) diverge from pDCs at the progenitor stage and mature into one of five different mDC populations currently identified [8,14].…”