Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow

Onai, Nobuyuki; Obata‐Onai, Aya; Schmid, Michael; Ohteki, Toshiaki; Jarrossay, David; Manz, Markus G.

doi:10.1038/ni1518

Cited by 604 publications

(655 citation statements)

References 49 publications

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“…The macrophage and DC precursor (MDP) for lymphoid tissue conventional DCs (cDCs), pDCs and monocytes is characterized as a cell expressing Lin À c-kit hi CD115 1 CX 3 CR1 1 Flt3 1 [8,26]. Another distinct progenitor is called the common DC precursor (CDP) (Lin À c-kit low CD115 1 Flt3 1 ) and is restricted to produce cDCs and pDCs, but not monocytes [27,28]. Preliminary data showed that ER-MP58 1 cells do not express Flt3 and do not produce pDCs when cultured in the presence of Flt3 in the fetal and pre-diabetic pancreas.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

et al. 2011

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The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. Before the start of lymphocytic insulitis, DC accumulation around islets of Langerhans is a hallmark for autoimmune diabetes development in this model. Previous experiments indicated that an inflammatory influx of these DCs in the pancreas is less plausible. Here, we investigated whether the pancreas contains DC precursors and whether these precursors contribute to DC accumulation in the NOD pancreas. Fetal pancreases of NOD and control mice were isolated followed by FACS using ER-MP58, Ly6G, CD11b and Ly6C. Sorted fetal pancreatic ER-MP58 1 cells were cultured with GM-CSF and tested for DC markers and antigen processing. CFSE labeling and Ki-67 staining were used to determine cell proliferation in cultures and tissues. Ly6C hi and Ly6C low precursors were present in fetal pancreases of NOD and control mice. These precursors developed into CD11c 1 MHCII 1 CD86 1 DCs capable of processing DQ-OVA. ER-MP58 1 cells in the embryonic and pre-diabetic NOD pancreas had a higher proliferation capacity. Our observations support a novel concept that pre-diabetic DC accumulation in the NOD pancreas is due to aberrant enhanced proliferation of local precursors, rather than to aberrant ''inflammatory infiltration'' from the circulation. IntroductionThe non-obese diabetic (NOD) mouse is used as a spontaneous model to study the development of type 1 diabetes [1]. Lymphocytes accumulate around and in the islets of Langerhans in NOD mice from around 6 weeks of age onwards, which results in the destruction of b-cells followed by a decrease in insulin production leading to diabetes. Prior to T-and B-cell accumulation the number of DCs increases in the pancreas and concentrates around the islets (from the age of 5 weeks onwards) [2,3]. DCs are potent APCs capable of stimulating both naïve and memory T cells [4]. The observation that DCs are the first immune cells to increase in number in the NOD pancreas points to a crucial role for DCs in the initiation of the islet autoimmune reaction. Such a role was recently proven by the demonstration that a temporal depletion of DCs totally abrogated the development of insulitis and diabetes in the NOD mouse model [5].Early studies have shown that BM precursors give rise to monocytes in blood, which circulate for a few days before they migrate into tissue where they develop into different types of DCs and macrophages. Blood monocytes can be subdivided into at least two subsets based on their Ly6C expression: classical and The nonclassical monocytes, which are Ly6C low , patrol the endothelium of the blood vessels and are required for rapid tissue invasion at the site of an infection [7]. Ly6C low monocytes are considered CD11c À , but some studies have reported the expression of CD11c on these cells [6,8]. Both types of monocytes are F4/80 1 and CD86 À [6].Data are accumulating on the presence of local tissue precursors for DCs and macrophages and the contribution of these precursors to DC and ma...

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Section: Discussionmentioning

confidence: 99%

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

et al. 2011

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“…Recently, these cells were termed monocyte-derived DCs (Mo-DCs) to discriminate them from classical and plasmacytoid DCs which are derived from a separate progenitor [48][49][50][51]. These Mo-DCs were characterized in particular under inflammatory conditions and include Tip-DCs (TNF-α-and iNOS-producing DCs), DC-SIGN + DCs and CX3CR1 + lamina propia DCs of the small intestine [23,48,52,53] (Fig.…”

Section: Development and Functions Of Macrophagesmentioning

confidence: 99%

Monocytes and Macrophages in Cancer: Development and Functions

Richards

Hettinger

Feuerer

2012

Cancer Microenvironment

171

122

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Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages, a very heterogeneous cell population in terms of phenotype and pro-tumor function, supporting tumor initiation, local progression and distant metastasis. Therefore, targeting monocytes and macrophages is a promising immunotherapeutic approach. This review will focus on the development of monocytes as macrophage precursors, the functions of tumorassociated macrophages and the possibility of interfering with tumor development and progression by targeting these myeloid cells.

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“…In mice it has been shown that conventional DC (cDC) and pDC can develop from minor Flt3 1 subpopulations within the common myeloid and the common lymphoid progenitor pools [5][6][7]. Recently, this pool was narrowed down to a DC committed precursor (pro-DC) that can only develop into cells of the DC lineages [8,9]. It is not clear yet at what point in DC development the commitment to a subpopulation is accomplished.…”

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confidence: 99%

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

et al. 2008

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Plasmacytoid dendritic cells (pDC) are central players in the innate and adaptive immune response against viral infections. The molecular mechanism that underlies pDC development from progenitor cells is only beginning to be elucidated. Previously, we reported that the Ets factor Spi-B and the inhibitors of DNA binding protein 2 (Id2) or Id3, which antagonize E-protein activity, are crucially involved in promoting or impairing pDC development, respectively. Here we show that the basic helix-loop-helix protein E2-2 is predominantly expressed in pDC, but not in their progenitor cells or conventional DC. Forced expression of E2-2 in progenitor cells stimulated pDC development. Conversely, inhibition of E2-2 expression by RNA interference impaired the generation of pDC suggesting a key role of E2-2 in development of these cells. Notably, Spi-B was unable to overcome the Id2 enforced block in pDC development and moreover Spi-B transduced pDC expressed reduced Id2 levels. This might indicate that Spi-B contributes to pDC development by promoting E2-2 activity. Consistent with notion, simultaneous overexpression of E2-2 and Spi-B in progenitor cells further stimulated pDC development. Together our results provide additional insight into the transcriptional network controlling pDC development as evidenced by the joint venture of E2-2 and Spi-B.Key words: E2-2/TCF4 Á E-proteins Á Human development Á Plasmacytoid dendritic cell Á Spi-B Supporting Information available online See accompanying commentary by Esashi and Liu IntroductionThe ability of dendritic cells (DC) to capture and present antigenic peptides has established a function in both the adaptive and innate branches of the immune system. Extensive characterization of DC has revealed the existence of many different DC subsets with distinct cell surface phenotype, cytokine expression profile, and anatomical localization [1]. One member of the DC family is the plasmacytoid DC (pDC), which is hallmarked by their capacity to produce high levels of type I interferons and hence are also known as natural type I interferons producing cells [2]. Eur. J. Immunol. 2008. 38: 2389-2400 DOI 10.1002 HIGHLIGHTS 2389Frontline pDC are detected in blood and most tissues, including spleen, lymph nodes, and thymus [2,3]. Previously, we described that at least two developmental pathways exist for pDC, an extrathymic and an intrathymic pathway [4]. The requirements for the development of DC subsets are not fully understood. In mice it has been shown that conventional DC (cDC) and pDC can develop from minor Flt3 1 subpopulations within the common myeloid and the common lymphoid progenitor pools [5][6][7]. Recently, this pool was narrowed down to a DC committed precursor (pro-DC) that can only develop into cells of the DC lineages [8,9]. It is not clear yet at what point in DC development the commitment to a subpopulation is accomplished. Also, human pDC can be derived from both myeloid and lymphoid progenitor cells [10,11]. A better understanding of the molecular mechanisms that control...

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Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow

Cited by 604 publications

References 49 publications

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Monocytes and Macrophages in Cancer: Development and Functions

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

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