Intrathymic and extrathymic development of human plasmacytoid dendritic cell precursors in vivo

Weijer, Kees; Uíttenbogaart, Christel H.; Voordouw, A. C.; Couwenberg, Franka; Seppen, Jurgen; Blom, Bianca; Vyth‐Dreese, Florry A.; Spits, Hergen

doi:10.1182/blood.v99.8.2752

Cited by 85 publications

(65 citation statements)

References 38 publications

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“…The BALB/c (H-2 d ) Rag2 À/À IL-2Rg c À/À mice 26 were bred and maintained in isolators, and were fed autoclaved food and water. Human fetal liver was obtained from elective abortions, with gestational age ranging from 14 to 18 weeks.…”

Section: Generation Of Human Immune System (His; Balb-rag/g) Mice Andmentioning

confidence: 99%

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

et al. 2009

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The efficient control of gene expression in vivo from lentiviral vectors remains technically challenging. To analyze inducible gene expression in a human setting, we generated 'human immune system' (HIS) mice by transplanting newborn BALB/c Rag2 À/À IL-2Rg c À/À immunodeficient mice with human hematopoietic stem cells transduced with a doxycyclineinducible lentiviral vector. We compared several methods of doxycycline delivery to mice, and could accurately measure doxycycline in vivo using a new sensitive detection assay. Two different lentiviral vector designs with constitutive (TRECMV-V14) or autoregulatory (TREAuto-V14) expression of an optimized reverse tetracycline transactivator were used to transduce human hematopoietic stem cells. After transplantation into immunodeficient mice, we analyzed the expression of the green fluorescent protein (GFP) reporter gene in the human hematopoiesis-derived cells that develop and accumulate in the generated HIS mice. We show efficient inducible GFP expression in adult HIS mice containing TREAuto-V14-transduced human cells, whereas GFP expression is poor with the TRECMV-V14 vector. Multiple cycles of doxycycline exposure in the TREAuto-V14 group result in repeated cycles of GFP expression with no loss of intensity. These findings are of major interest for gene therapy and basic research settings that require inducible gene expression.

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Section: Generation Of Human Immune System (His; Balb-rag/g) Mice Andmentioning

confidence: 99%

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

et al. 2009

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“…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.…”

Section: Introductionmentioning

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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“…We established several donor/host experimental groups: B6.GFP ϩ cells into B6 recipient mice, B6.CD45.1 cells into B6 mice, and B6.CD45.1 cells into RAG-2/␥ chain Ϫ/Ϫ mice (14). CD45.1 donor-derived CD19 high CD45R Ϫ/low B cells could be followed because, although lacking the CD45R isoform, they had a normal expression of the common CD45 leukocyte Ag (data not shown).…”

Section: The Population Of Cd19mentioning

confidence: 99%

A Population of CD19highCD45R−/lowCD21low B Lymphocytes Poised for Spontaneous Secretion of IgG and IgA Antibodies

Andrés

Cortegano

Serrano

et al. 2007

The Journal of Immunology

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Ab responses to selected Ags are produced by discrete B cell populations whose presence and functional relevance vary along the ontogeny. The earliest B lineage-restricted precursors in gestational day 11 mouse embryos display the CD19+CD45R/B220− phenotype. Phenotypically identical cells persist throughout gestation and in postnatal life, in parallel to the later-arising, CD19+CD45R+ B cells. Very early after birth, the CD19+CD45R− B cell subset included high frequencies of spontaneously Ig-secreting cells. In the adult spleen, a small subset of CD19highCD45R−/lowIgM+/−IgD−CD21/Cr2−/low cells, which was detected in perifollicular areas, displayed genetic and phenotypical traits of highly differentiated B cells, and was enriched in IgG- and IgA-secreting plasma cells. In vitro differentiation and in vivo adoptive transfer experiments of multipotent hemopoietic progenitors revealed that these CD19highCD45R−/low B cells were preferentially regenerated by embryo-, but not by adult bone marrow-, derived progenitors, except when the latter were inoculated into newborn mice. Both the early ontogenical emergence and the natural production of serum Igs, are shared features of this CD19highCD45R−/low B cell population with innate-like B lymphocytes such as B1 and marginal zone B cells, and suggest that the new population might be related to that category.

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Intrathymic and extrathymic development of human plasmacytoid dendritic cell precursors in vivo

Cited by 85 publications

References 38 publications

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

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

A Population of CD19highCD45R−/lowCD21low B Lymphocytes Poised for Spontaneous Secretion of IgG and IgA Antibodies

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