The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis

• Published in: Blood 2009-07, Vol.114 (4), p.835-843
• Main Authors: Kingston, Dior, Schmid, Michael A., Onai, Nobuyuki, Obata-Onai, Aya, Baumjohann, Dirk, Manz, Markus G.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Marrow Cells - physiology; Cell Proliferation; Dendritic Cells - metabolism; Dendritic Cells - physiology; Female; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene Expression - physiology; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Granulocyte-Macrophage Colony-Stimulating Factor - physiology; Hematologic and hematopoietic diseases; Homeostasis - genetics; Immunity, Innate - genetics; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Specificity - genetics; Receptor, Macrophage Colony-Stimulating Factor - genetics; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Stem Cells - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-02-206318

Dendritic cell (DC) development is efficiently supported by Flt3-ligand or GM-CSF in vitro, and lymphoid-organ DC maintenance in vivo is critically dependent on Flt3-ligand. However, the relevance of GM-CSF for lymphoid-tissue DC maintenance and the importance of both cytokines for nonlymphoid organ DC homeostasis are not defined. Here, we show that, although Gm-csfr and Flt3 are both expressed in DC progenitors, Gm-csfr is expressed predominantly in monocytes, classical DCs (cDCs), and skin DCs, whereas Flt3 is expressed in both cDCs and plasmacytoid DCs (pDCs). In accordance with the respective cytokine receptor expression, DC progenitor and pDC numbers are primarily affected by Flt3-ligand deficiency, whereas both splenic and lymph node cDCs and dermal DCs are reduced in the absence of either GM-CSF or Flt3-ligand. Combined lack of GM-CSF and Flt3-ligand in newly generated double-deficient mice leads to further significant reductions of DC progenitors and dermal DCs. In line with the decrease of respective DC subsets, T-cell and antigen-specific IgG responses decline progressively, from wild-type to GM-CSF– to Flt3-ligand– to double-deficient mice, upon subcutaneous antigen delivery. These data thus show the concerted action of GM-CSF and Flt3-ligand on DC homeostasis in vivo.