Plasmacytoid Dendritic Cells Activate Lymphoid-Specific Genetic Programs Irrespective of Their Cellular Origin

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Immunity (Impact Factor: 21.56). 08/2004; 21(1):43-53. DOI: 10.1016/j.immuni.2004.06.011
Source: PubMed


The developmental origin of type I interferon (IFN)-producing plasmacytoid dendritic cells (PDCs) is controversial. In particular, the rearrangement of immunoglobulin heavy chain (IgH) genes in murine PDCs and the expression of pre-T cell receptor alpha (pTalpha) gene by human PDCs were proposed as evidence for their "lymphoid" origin. Here we demonstrate that PDCs capable of IFN production develop efficiently from both myeloid- and lymphoid-committed progenitors. Rearranged IgH genes as well as RAG transcripts were found in both myeloid- and lymphoid-derived PDCs. The human pTalpha transgenic reporter was activated in both myeloid- and lymphoid-derived PDCs at a level comparable to pre-T cells. PDCs were the only cell population that activated murine RAG1 knockin and human pTalpha transgenic reporters outside the lymphoid lineage. These results highlight a unique developmental program of PDCs that distinguishes them from other cell types including conventional dendritic cells.

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    • "pDCs are short-lived and require constant replenishment from their precursors in the BM. DCs, including pDCs, are generated from Flt3- expressing progenitors of myeloid lineages, including common myeloid progenitor (CMP), macrophage/DC progenitor, and common dendritic progenitor (CDP), and of lymphoid lineages such as common lymphoid progenitor (CLP; D'Amico and Wu, 2003; Karsunky et al., 2003; Shigematsu et al., 2004; Naik et al., 2007; Onai et al., 2007; Liu et al., 2009). Targeted deletion of Flt3 or FL in mice leads to reduced numbers of DC progenitors and impaired DC development (McKenna et al., 2000; Waskow et al., 2008). "
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    ABSTRACT: During infections and inflammation, plasmacytoid dendritic cells (pDCs) are the most potent type I interferon (IFN-I)-producing cells. However, the developmental origin of pDCs and the signals dictating pDC generation remain incompletely understood. Here, we report a synergistic role for IFN-I and Flt3 ligand (FL) in pDC development from common lymphoid progenitors (CLPs). Both conventional DCs (cDCs) and pDCs were generated from CLPs in response to FL, whereas pDC generation required higher concentrations of FL and concurrent IFN-I signaling. An absence of IFN-I receptor, impairment of IFN-I signaling, or neutralization of IFN-I significantly impeded pDC development from CLPs. Furthermore, FL induced IFN-I expression in CLPs, which in turn induced Flt3 up-regulation that facilitated survival and proliferation of CLPs, as well as their differentiation into pDCs. Collectively, these results define a critical role for the FL/IFN-I/Flt3 axis in pDC differentiation from CLPs.
    Journal of Experimental Medicine 10/2013; 210(12). DOI:10.1084/jem.20130536 · 12.52 Impact Factor
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    • "Besides a set of lymphoid-specific genes including Rag, Dntt and VpreB [32], pDCs also express CD45R/B220, a B cell-specific surface marker [53]. Rag expression in pDCs is functional, as pDCs undergo partial (D-J) rearrangement at the immunoglobulin heavy chain locus [32], a hallmark of early developing B cells. Moreover, the BDCA2 receptor on pDCs has been shown to signal through signaling components of the B cell receptor, including Syk and SLP-65 [54,55]. "
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    ABSTRACT: Growth factor independence genes (Gfi1 and Gfi1b) repress recombination activating genes (Rag) transcription in developing B lymphocytes. Because all blood lineages originate from hematopoietic stem cells (HSCs) and different lineage progenitors have been shown to share transcription factor networks prior to cell fate commitment, we hypothesized that GFI family proteins may also play a role in repressing Rag transcription or a global lymphoid transcriptional program in other blood lineages. We tested the level of Rag transcription in various blood cells when Gfi1 and Gfi1b were deleted, and observed an upregulation of Rag expression in plasmacytoid dendritic cells (pDCs). Using microarray analysis, we observed that Gfi1 and Gfi1b do not regulate a lymphoid or pDC-specific transcriptional program. This study establishes a role for Gfi1 and Gfi1b in Rag regulation in a non-B lineage cell type.
    PLoS ONE 09/2013; 8(9):e75891. DOI:10.1371/journal.pone.0075891 · 3.23 Impact Factor
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    • "The pDCs derive from the common dendritic progenitors (CDP) which express FLT3-R (CD135), CSF1-R (CD115), and low levels of c-kit (CD117) (Onai et al., 2007). Alternatively, pDCs may derive from lymphoid progenitors (Shigematsu et al., 2004; Luo and Lei, 2012; Sathe et al., 2013). Differentiation of pDCs relies essentially on Flt3-L which allows the expansion of cDC/pDC common progenitors and contributes to peripheral DC homeostasis (Waskow et al., 2008; Eidenschenk et al., 2010). "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a particular subset of DCs that link innate and adaptive immunity. They are responsible for the substantial production of type 1 interferon (IFN-I) in response to viral RNA or DNA through activation of TLR7 and 9. Furthermore, pDCs present antigens (Ag) and induce naïve T cell differentiation. It has been demonstrated that pDCs can induce immunogenic T cell responses through differentiation of cytotoxic CD8(+) T cells and effector CD4(+) T cells. Conversely, pDCs exhibit strong tolerogenic functions by inducing CD8(+) T cell deletion, CD4(+) T cell anergy, and Treg differentiation. However, since IFN-I produced by pDCs efficiently activates and recruits conventional DCs, B cells, T cells, and NK cells, pDCs also indirectly affect the nature and the amplitude of adaptive immune responses. As a consequence, the precise role of Ag-presenting functions of pDCs in adaptive immunity has been difficult to dissect in vivo. Additionally, different experimental procedures led to conflicting results regarding the outcome of T cell responses induced by pDCs. During the development of autoimmunity, pDCs have been shown to play both immunogenic and tolerogenic functions depending on disease, disease progression, and the experimental conditions. In this review, we will discuss the relative contribution of innate and adaptive pDC functions in modulating T cell responses, particularly during the development of autoimmunity.
    Frontiers in Immunology 03/2013; 4:59. DOI:10.3389/fimmu.2013.00059
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