Developmental origin of interferon-alpha-producing dendritic cells from hematopoietic precursors

Department of Developmental Biology , Stanford University, Palo Alto, California, United States
Experimental Hematology (Impact Factor: 2.81). 03/2005; 33(2):173-81. DOI: 10.1016/j.exphem.2004.10.010
Source: PubMed

ABSTRACT The aim of this study was to determine the lineage origin of interferon-alpha-producing cells (IPCs), also called plasmacytoid dendritic cells, in mice by evaluating the ability of common lymphoid (CLP) and myeloid (CMP) progenitors to give rise to IPCs.
Sublethally irradiated C57Bl/6 mice were intravenously transplanted with rigorously purified lymphoid and myeloid progenitors from a congenic mouse strain. At various time points posttransplantation mice were analyzed for donor-derived cells by flow cytometry. The developmental potential of all progenitor populations was also tested in in vitro cultures. In addition, in vitro and in vivo derived IPCs were functionally assessed for their interferon-alpha production after virus challenge.
Transplantation of 1 x 10(4) common myeloid progenitors, 1 x 10(4) common lymphoid progenitors or 2.5 x 10(4) granulocyte/macrophage progenitors all led to the generation of IPCs within 2 to 3 weeks. In general, IPC reconstitution in spleen and liver by CMPs was more efficient than by CLP. Adding Flt3L alone to in vitro cultures was sufficient to support the development of IPCs from myeloid progenitors whereas CLPs required additional survival factors provided either by stroma cells or by introduction of transgenic Bcl-2. Both myeloid- and lymphoid-derived IPC were indistinguishable by function, gene expression, and morphology.
Surprisingly, our results clearly show that murine IPCs differentiate from both lineages but are mainly of myeloid origin. These results extend to IPCs the observation made originally in classical dendritic cells that cellular expression of so called lineage markers does not correlate with lineal origin.

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Taken together, this research identified some of the key steps in the development of DCs downstream of the early haematopoietic precursors. It also dissected the contribution of different precursors for the Langerhans cell development in both the steady-state and during inflammation. Finally it provides evidence for the importance of Id2 and E proteins, such as E47 working in concert to regulate DC development and differentiation. Dendritische Zellen gehören zu den professionellen antigenpräsentierenden Zellen, die Antigene aufnehmen und in das Lymphgewebe wandern, wo sie antigenspezifische Immunreaktionen initiieren. Verschiedene Subtypen von Dendritischen Zellen wurden bereits charakterisiert, abhängig von ihrer Funktion und Lokalisation. Jeder dieser Subtypen scheint eine besondere Rolle, sowohl in Immunität als auch in Toleranz zu haben. Hingegen ist es weniger klar, wie sich diese verschiedenen Subtypen von Dendritischen Zellen aus ihren hämatopoetischen Vorläufern entwickeln und welche molekularen Mechanismen an der Regulation der verschiedenen Entwicklungsstufen beteiligt sind. Die vorliegende Arbeit hatte das Ziel einen bereits beschriebenen Vorläufer für Dendritische Zellen, den sogenannten „Flt3+ progenitor“, weiterführend zu charakterisieren und sein Entwicklungspotenzial in vivo zu untersuchen. Dabei zeigte sich, dass der „Flt3+ progenitor“ nicht nur Dendritische Zellen bildet, sondern sich auch in alle anderen Zellen des hämatopoetischen Systems entwickeln kann. Des Weiteren bearbeitet diese Studie den Einfluss des HLH Transkriptionsfaktors Id2 auf die Entwicklung von verschiedenen Subtypen Dendritischer Zellen, insbesondere Langerhans Zellen. 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