Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate

Abstract

Dendritic cells (DCs) and monocytes develop from a series of bonemarrow-resident progenitors in which lineage potential is regulated by distinct transcription factors. Zeb2 is an E-box-binding protein associated with epithelial-mesenchymal transition and is widely expressed among hematopoietic lineages. Previously, we observed that Zeb2 expression is differentially regulated in progenitors committed to classical DC (cDC) subsets in vivo. Using systems for inducible gene deletion, we uncover a requirement for Zeb2 in the development of Ly-6C hi monocytes but not neutrophils, and we show a corresponding requirement for Zeb2 in expression of the M-CSF receptor in the bone marrow. In addition, we confirm a requirement for Zeb2 in development of plasmacytoid DCs but find that Zeb2 is not required for cDC2 development. Instead, Zeb2 may act to repress cDC1 progenitor specification in the context of inflammatory signals. + cDCs that function in crosspresentation of viral antigen and defense against intracellular pathogens. The cDC2 subset includes heterogeneous populations of CD172a (Sirp-α) + cDCs that promote T H 17-type responses to bacteria and fungi and T H 2-type responses to parasites. Plasmacytoid DCs (pDCs) are a lineage distinct from cDCs identified by surface expression of CD45R (B220), Siglec-H, and CD317 (Bst2). They do not function directly in T-cell priming (3) but are specialized for production of large quantities of type I IFN in response to infection (4-6).DCs arise from a series of progenitors with progressively restricted potential (1). Within lineage (Lin)

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

“…For example, the most highly expressed transcript in CD154 + cells versus CD154 − cells encodes a cytoskeletal protein called Ermin (ERMN), which is believed to be restricted to oligodendrocytes [31]. Similarly, the most highly expressed gene for a transcription factor in CD154 + versus CD154 − cells encodes Zinc Finger E-Box Binding Homeobox 2 (ZEB2), which has been implicated in CD8 + T cell and myeloid cell function but to our knowledge has not been investigated for its potential functions in CD4 + T cells [32, 33]. …”

“…While ZEB2 was shown to be downstream of T-bet, and these two factors co-regulate many of the same genes, it appears that ZEB2 modulates these downstream genes independently. Given that ZEB2 plays a similar role in the maturation Natural Killer cells [50], and is required for the development of plasmacytoid dendritic cells and monocytes [33], it would be relevant to assess whether ZEB2 has similar functions in the differentiation of CD4 + T cells.…”

ZEBs: Novel Players in Immune Cell Development and Function

“…Stimulated by these findings, we and others, used various conditional genetic approaches, including the Itgax-Cre (CD11c-Cre) and Mx1-Cre models crossed to Zeb2 fl/fl mice, to examine the requirement for ZEB2 expression by DCs [7,14]. pDCs were found to require ZEB2 in a dose-dependent manner for their development and/or maintenance in tissues ( Figure 3), and loss of one or both copies of Zeb2 resulted in a reduction or loss of splenic pDCs, respectively, compared with wild-type (WT) controls [7,14]. In addition, retrovirus-driven overexpression of Zeb2 in Kit hi bone marrow (BM) progenitors increased pDC numbers following in vitro treatment with FMS-like tyrosine kinase 3 ligand (Flt3L), relative to control cultures [7] (Figure 3).…”

“…pDCs were found to require ZEB2 in a dose-dependent manner for their development and/or maintenance in tissues ( Figure 3), and loss of one or both copies of Zeb2 resulted in a reduction or loss of splenic pDCs, respectively, compared with wild-type (WT) controls [7,14]. In addition, retrovirus-driven overexpression of Zeb2 in Kit hi bone marrow (BM) progenitors increased pDC numbers following in vitro treatment with FMS-like tyrosine kinase 3 ligand (Flt3L), relative to control cultures [7] (Figure 3). In terms of mechanism, Zeb2 deletion in both models resulted in increased expression of inhibitor of DNA binding 2 (Id2) compared with control pDCs [14].…”

“…In recent years investigations of the role of ZEBs in the hematopoietic compartment have been initiated, and it is now clear that ZEB2 is crucial for mammalian embryonic development [5]. Moreover, loss of ZEB2 specifically in the murine adult hematopoietic system results (after 10-12 months) in splenomegaly with the enlarged spleens containing a significant infiltration of hematopoietic stem cells and megakaryocyte/erythroid progenitor cells, indicative of extramedullary hematopoiesis [6,7]. In addition, within the murine immune system, ZEBs have been implicated in the development, differentiation, and maintenance of various cell types.…”