Flk2(+) myeloid progenitors are the main source of Langerhans cells

Stanford University, Palo Alto, California, United States
Blood (Impact Factor: 10.43). 03/2006; 107(4):1383-90. DOI: 10.1182/blood-2005-05-1878
Source: PubMed

ABSTRACT Langerhans cells (LCs) are antigen-presenting cells (APCs) residing in the epidermis that play a major role in skin immunity. Our earlier studies showed that when skin is inflamed LCs are replaced by bone marrow-derived progenitor cells, while during steady-state conditions LCs are able to self-renew in the skin. Identification of the LC progenitors in bone marrow would represent a critical step toward identifying the factors that regulate LC generation as well as their trafficking to the skin. To determine LC lineage origin, we reconstituted lethally irradiated CD45.2 mice with rigorously purified lymphoid and myeloid progenitors from CD45.1 congenic mice. Twenty-four hours later, we exposed the mice to UV light to deplete resident LCs and induce their replacement by progenitors. Reconstitution with common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-macrophage progenitors (GMPs), or early thymic progenitors led to LC generation within 2 to 3 weeks. CMPs were at least 20 times more efficient at generating LCs than CLPs. LCs from both lineages were derived almost entirely from fetal liver kinase-2+ (Flk-2+) progenitors, displayed typical dendritic-cell (DC) morphology, and showed long-term persistence in the skin. These results indicate that LCs are derived mainly from myeloid progenitors and are dependent on Flt3-ligand for their development.

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Available from: Miriam Merad, Oct 24, 2014
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    ABSTRACT: Dendritic cells are professional antigen presenting cells that capture antigens and migrate to lymphoid tissues where they elicit specific immune responses. Several DC subtypes have previously been characterised, depending on their function and location. Each subtype appears to have a specialised role in both immunity and tolerance. However, less clear are the processes by which these different DC subsets develop from haematopoietic precursors, and the molecular mechanisms involved in the regulation of the different stages during DC development. The research described herein had the aim to continuatively characterize a previously described DC precursor, the Flt3+ progenitor, downstream of the haematopoietic stem cells, and to assess its developmental potential in vivo. Hereby, it was found that the Flt3+ progenitor does not only develop into dendritic cells, but can also generate all other cells of the haematopoietic compartment. Furthermore, this study examined the role of the HLH transcriptional regulator Id2 on the development of different DC subtypes, especially Langerhans cells. As monocytes had been assumed to be LC precursors, Gr-1hi monocytes as well as the Flt3+ progenitor were tested for their LC precursor potential. Using an Id2 knockout mouse model, it was found that Id2 is essential for the formation of Langerhans cells in steady state. Conversely, their development from Gr-1hi monocytes in response to inflammation is independent of Id2. Id2 is known to modulate the activity of E-proteins, such as E47, by antagonising their DNA binding. Therefore, the impact of Id2 and E47 on DC development was studied and this work provides new insights into the molecular mechanisms controlling the development of distinct DC subsets. It shows that the molecular mechanism by which Id2 controls the development of different DC subtypes is based on a modulation of E-proteins. 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. Da bereits gezeigt wurde, dass Monozyten Vorläufer der Langerhans Zellen sein können, wurden Gr-1hi Monozyten sowie der „Flt3+ progenitor“ auf ihre Fähigkeit Langerhans Zellen zu bilden untersucht. Dafür wurde ein Mausmodell verwendet, in dem Id2 genetisch inaktiviert war. Hierbei wurde gefunden, dass Id2 unter normalen Bedingungen essentiell für die Bildung von Langerhans Zellen ist, während deren Bildung aus Gr-1hi Monozyten in Antwort auf eine Entzündung unabhängig von Id2 verläuft. Es ist bekannt, dass Id2 die Aktivität von E-Proteinen, wie zum Beispiel E47, verändert, indem es ihre Bindung an DNS verhindert. Daher wurde der Einfluss von Id2 und E47 auf die Entwicklung von Dendritischen Zellen analysiert und diese Arbeit zeigt, dass der molekulare Mechanismus, durch den Id2 die Entwicklung von verschiedenen Subtypen Dendritischer Zellen kontrolliert, auf einer Beeinflussung von E-Proteinen basiert. Zusammen genommen identifiziert diese Arbeit einige der wesentlichen Schritte in der Entwicklung von Dendritischen Zellen aus frühen hämatopoetischen Vorläuferzellen. Weiterhin betrachtet sie den Beitrag verschiedener Vorläufer zur Entwicklung von Langerhans Zellen, sowohl im Normalzustand, als auch während der Entzündung. Abschließend zeigt sie die Bedeutung des Zusammenspiels von Id2 und E-Proteinen, wie zum Beispiel E47, in der Entwicklung und Differenzierung von Dendritischen Zellen.
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    ABSTRACT: Flt3 ligand (Flt3L) is a nonredundant cytokine in type I interferon-producing cell (IPC) and dendritic cell (DC) development, and IPC and DC differentiation potential is confined to Flt3+ hematopoietic progenitor cells. Here, we show that overexpression of human Flt3 in Flt3- (Flt3(-)Lin(-)IL-7Ralpha(-)Thy1.1(-)c-Kit+) and Flt3+ (Flt3(+)Lin(-)IL-7Ralpha(-)Thy1.1(-)c-Kit+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. In defined hematopoietic cell populations, such as Flt3- megakaryocyte/erythrocyte-restricted progenitors (MEPs), enforced Flt3 signaling induces transcription of IPC, DC, and granulocyte/macrophage (GM) development-affiliated genes, including STAT3, PU.1, and G-/M-/GM-CSFR, and activates differentiation capacities to these lineages. Moreover, ectopic expression of Flt3 downstream transcription factors STAT3 or PU.1 in Flt3- MEPs evokes Flt3 receptor expression and instructs differentiation into IPCs, DCs, and myelomonocytic cells, whereas GATA-1 expression and consecutive megakaryocyte/erythrocyte development is suppressed. Based on these data, we propose a demand-regulated, cytokine-driven DC and IPC regeneration model, in which high Flt3L levels initiate a self-sustaining, Flt3-STAT3- and Flt3-PU.1-mediated IPC and DC differentiation program in Flt3+ hematopoietic progenitor cells.
    Journal of Experimental Medicine 02/2006; 203(1):227-38. DOI:10.1084/jem.20051645 · 13.91 Impact Factor
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