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Regulatory mechanisms in early dendritic cell development
- Abstract
- Dendritic cells (DCs) are essential immune cells for antigen presentation and are responsible for the initiation of T-cell responses. With the exception of Langerhans cells, all subtypes of DCs are derived from bone marrow-resident hematopoietic stem cells (HSCs). DCs develop from HSCs via several specification steps and intermediate progenitor stages including common myeloid progenitor (CMP) and the monocyte/DC progenitor (MDPs) stages.
The transcription factor C/EBPa (CCAAT/enhancer binding protein alpha) is known to play an important role in early hematopoiesis. Mice with a homozygous deletion of the Cebpa gene have normal to elevated numbers of CMPs but completely lack granulocytic/monocytic progenitors (GMPs) and all subsequent granulocytic stages indicating that C/EBPa is essential for transition of early myeloid to late myeloid progenitors. Despite its critical role in early myeloid and hence DC progenitors little is known about C/EBPa in early DC development.
Preliminary results from our lab using an inducible bone marrow-specific Cebpa knock-out mouse model (Mx1-Cre CebpaF/F) suggest that C/EBPa indeed has an important role in early DC development. Mice lacking Cebpa in the bone marrow display reduced numbers of both subtypes of conventional DCs (cDCs) in spleen, and even more prominent in lymph nodes and thymus, while plasmacytoid DCs are not affected. The fact that cDCs are formed albeit at reduced numbers indicates that C/EBPa is dispensable for cDC formation but is crucially involved in proliferation and/or inhibition of apoptosis in cDC precursors. In addition, it is currently not known whether cDCs formed in the absence of C/EBPa display full functional activity. Using gene expression profiling we have identified a number of C/EBPa target genes in early DC progenitors including other transcription factors, inflammatory cytokines, genes of the NF-kB-pathway, genes associated with DC maturation and distinct anti-apoptotic factors. Based on these results the aim of this project is to identify critical factors involved in differentiation, proliferation and/or inhibition of apoptosis in early DC progenitors affected by C/EBPa. To experimentally approach this goal we will use Mx1-Cre CebpaF/F experimental and Mx1-Cre Cebpawt/wt control mice and analyze DCs in spleen, lymph nodes and thymus for expression of various DC-specific surface antigens and - after isolation characterize their function. In addition, isolated FLT3+ myeloid progenitors of these mice will be stimulated with FLT3L and monitored in vitro for changes in gene expression and functionality at critical steps during DC formation.
- Keywords
- cancer research
- Stem cell research
- haematology
- immunology
- Project Leader:
- Wölfler Albert
- Duration:
- 01.08.2013-30.06.2020
- Type of Research
- basic research
- Staff
- Wölfler, Albert, Project Leader
- Schlacher, Angelika, Co-worker
- Daga, Shruti, Co-worker
- Muralikrishnan, Anirudh Subramanian, Co-worker
- Schaefer, Carolin, Co-worker
- MUG Research Units
- Division of Haematology
- Division of Rheumatology and Immunology