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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2446-2452.
Prepublished online as a Blood First Edition Paper on November 29, 2005; DOI 10.1182/blood-2005-05-2090.
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IMMUNOBIOLOGY
Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B
Wendy Dontje,
Remko Schotte,
Tom Cupedo,
Maho Nagasawa,
Ferenc Scheeren,
Ramon Gimeno,
Hergen Spits, and
Bianca Blom
From the Department of Cell Biology and Histology of the Academic Medical Center (AMC) at the University of Amsterdam, The Netherlands.
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+TCR  + 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. (Blood. 2006;107:2446-2452)
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