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

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 and Tom Taghon ()
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Inge Van de Walle: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Anne-Catherine Dolens: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Kaat Durinck: Center for Medical Genetics, Ghent University, University Hospital Ghent
Katrien De Mulder: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Wouter Van Loocke: Center for Medical Genetics, Ghent University, University Hospital Ghent
Sagar Damle: California Institute of Technology
Els Waegemans: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Jelle De Medts: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Imke Velghe: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Magda De Smedt: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Bart Vandekerckhove: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Tessa Kerre: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Jean Plum: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Georges Leclercq: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent
Ellen V. Rothenberg: California Institute of Technology
Pieter Van Vlierberghe: Center for Medical Genetics, Ghent University, University Hospital Ghent
Frank Speleman: Center for Medical Genetics, Ghent University, University Hospital Ghent
Tom Taghon: Faculty of Medicine and Health Sciences, Microbiology and Immunology, Ghent University, University Hospital Ghent

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11171

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