Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B.
Human early thymic precursors have the potential to differentiate into multiple cell lineages, including T cells and plasmacytoid dendritic cells (pDCs). This decision is guided by the induction or silencing of lineage-specific transcription factors. The ETS family member Spi-B is a key regulator of pDC development, whereas T-cell development is critically dependent on GATA-3. Here we show that triggering of the Notch1 signaling pathway by Delta-like1 controls the T/pDC lineage decision by regulating the balance between these factors. CD34+ CD1a- thymic progenitor cells express Notch1, but down-regulate this receptor when differentiating into pDCs. On coculture with stromal cell lines expressing either human Delta-like1 (DL1) or Jagged1 (Jag1) Notch ligands, thymic precursors express GATA-3 and develop into CD4+ CD8+ TCRalphabeta+ T cells. On the other hand, DL1, but not Jag1, down-regulates Spi-B expression, resulting in impaired development of pDCs. The Notch1-induced block in pDC development can be relieved through the ectopic expression of Spi-B. These data indicate that DL1-induced activation of the Notch1 pathway controls the lineage commitment of early thymic precursors by altering the levels between Spi-B and GATA-3.
Dontje
Wendy
W
Department of Cell Biology and Histology of the AMC, University of Amsterdam, The Netherlands.
Schotte
Remko
R
Cupedo
Tom
T
Nagasawa
Maho
M
Scheeren
Ferenc
F
Gimeno
Ramon
R
Spits
Hergen
H
Blom
Bianca
B
D018952:Antigens, CD34; D002135:Calcium-Binding Proteins / Q000502:physiology; D019070:Cell Lineage; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics*; D003713:Dendritic Cells / Q000166:cytology*; D050990:GATA3 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000502:physiology*; D051881:Receptor, Notch1 / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics*
D018952:Antigens, CD34; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C076877:SPIB protein, human