Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B

Blood. 2006 Mar 15;107(6):2446-52. doi: 10.1182/blood-2005-05-2090. Epub 2005 Nov 29.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34
  • Calcium-Binding Proteins / physiology
  • Cell Lineage*
  • Coculture Techniques
  • DNA-Binding Proteins / genetics*
  • Dendritic Cells / cytology*
  • GATA3 Transcription Factor / genetics*
  • Gene Expression Regulation
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Membrane Proteins / physiology*
  • Receptor, Notch1 / physiology*
  • Repressor Proteins / physiology*
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Stromal Cells / cytology
  • T-Lymphocytes / cytology*
  • Transcription Factors / genetics*

Substances

  • Antigens, CD34
  • Calcium-Binding Proteins
  • DLK1 protein, human
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Repressor Proteins
  • Serrate-Jagged Proteins
  • Transcription Factors
  • SPIB protein, human