GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate.

نویسندگان

  • Inge Van de Walle
  • Anne-Catherine Dolens
  • Kaat Durinck
  • Katrien De Mulder
  • Wouter Van Loocke
  • Sagar Damle
  • Els Waegemans
  • Jelle De Medts
  • Imke Velghe
  • Magda De Smedt
  • Bart Vandekerckhove
  • Tessa Kerre
  • Jean Plum
  • Georges Leclercq
  • Ellen V Rothenberg
  • Pieter Van Vlierberghe
  • Frank Speleman
  • Tom Taghon
چکیده

The gradual reprogramming of haematopoietic precursors into the T-cell fate is characterized by at least two sequential developmental stages. Following Notch1-dependent T-cell lineage specification during which the first T-cell lineage genes are expressed and myeloid and dendritic cell potential is lost, T-cell specific transcription factors subsequently induce T-cell commitment by repressing residual natural killer (NK)-cell potential. How these processes are regulated in human is poorly understood, especially since efficient T-cell lineage commitment requires a reduction in Notch signalling activity following T-cell specification. Here, we show that GATA3, in contrast to TCF1, controls human T-cell lineage commitment through direct regulation of three distinct processes: repression of NK-cell fate, upregulation of T-cell lineage genes to promote further differentiation and restraint of Notch activity. Repression of the Notch1 target gene DTX1 hereby is essential to prevent NK-cell differentiation. Thus, GATA3-mediated positive and negative feedback mechanisms control human T-cell lineage commitment.

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عنوان ژورنال:
  • Nature communications

دوره 7  شماره 

صفحات  -

تاریخ انتشار 2016