Abstract
Dendritic cells (DCs) comprise heterogenous and functionally diverse populations of antigen presenting cells. Their developmental pathways remain largely unknown. Using a transcriptional profiling approach, we identified Gfi1 as a novel critical transcription factor in GM-CSF-dependent DC differentiation. Gfi1 is expressed in precursor and mature DCs, as seen in Gfi+/GFP mice, in which one Gfi1 allele is replaced by the GFP cDNA.
Gfi1−/ − mice showed a global reduction of myeloid and lymphoid DCs in all lymphoid organs whereas epidermal Langerhans cells were enhanced in number. Gfi1−/ − DCs showed marked phenotypic and functional alterations, as exemplified by decreased MHC class II expression, absent upregulation of costimulatory molecules upon stimulation and reduced ability to stimulate specific T-cell responses. In contrast, Gfi1−/ − DCs exhibited an increased activation profile as assessed by enhanced secretion of IL12. In vitro, Gfi1−/ − hematopoietic progenitor cells were unable to develop into DCs in the presence of GM-CSF or Flt3L. Instead, they differentiated into macrophages, as evidenced by morphology, expression of cell surface markers, and functional properties. These findings suggest that Gfi1 is a critical modulator of DC versus macrophage development. Analysis of hematopoietic chimeras upon transplantation into congenic recipient mice established a cell-autonomous and non-redundant role for Gfi1 in DC development. Furthermore, upon retroviral gene transfer into Gfi1−/ − progenitor cells, the developmental defect could be reconstituted in vitro and in vivo. The inability of Gfi1−/ − hematopoietic progenitor cells to develop into DCs was associated with decreased STAT3 activation, as shown by Western blot and EMSA assays. In conclusion, we have identified Gfi1 as a critical transcription factor that controls DC versus macrophage development and dissociates DC maturation and -activation.
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