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An early decrease in Notch activation is required for human TCR-αβ lineage differentiation at the expense of TCR-γδ T cells

Inge Van de Walle UGent, Greet De Smet UGent, Magda De Smedt UGent, Bart Vandekerckhove UGent, Georges Leclercq UGent, Jean Plum UGent and Tom Taghon UGent (2009) BLOOD. 113(13). p.2988-2998
abstract
Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor alpha beta (TCR-alpha beta) versus TCR-gamma delta lineage decision is still unclear. Although it is clear in the mouse that TCR-gamma delta development is less Notch dependent compared with TCR-alpha beta differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and gamma delta T cells but inhibits differentiation toward the alpha beta lineage. Reducing the amount of Notch activation rescues alpha beta-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity in-creases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during alpha beta-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-gamma delta development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.
Please use this url to cite or link to this publication:
author
organization
alternative title
An early decrease in Notch activation is required for human TCR-alpha beta lineage differentiation at the expense of TCR-gamma delta T cells
year
type
journalArticle (original)
publication status
published
subject
keyword
B-CELL, PROGENITOR CELLS, THYMUS MICROENVIRONMENT, BETA/GAMMA-DELTA, FATE, C-MYC, GENE-EXPRESSION, IN-VITRO, ANKYRIN-REPEAT PROTEIN, SIGNALING PATHWAY
journal title
BLOOD
Blood
volume
113
issue
13
pages
2988 - 2998
Web of Science type
Article
Web of Science id
000264559000017
JCR category
HEMATOLOGY
JCR impact factor
10.555 (2009)
JCR rank
2/61 (2009)
JCR quartile
1 (2009)
ISSN
0006-4971
DOI
10.1182/blood-2008-06-164871
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
604628
handle
http://hdl.handle.net/1854/LU-604628
date created
2009-04-30 15:40:17
date last changed
2011-04-14 10:38:46
@article{604628,
  abstract     = {Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor alpha beta (TCR-alpha beta) versus TCR-gamma delta lineage decision is still unclear. Although it is clear in the mouse that TCR-gamma delta development is less Notch dependent compared with TCR-alpha beta differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and gamma delta T cells but inhibits differentiation toward the alpha beta lineage. Reducing the amount of Notch activation rescues alpha beta-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity in-creases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during alpha beta-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-gamma delta development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.},
  author       = {Van de Walle, Inge and De Smet, Greet and De Smedt, Magda and Vandekerckhove, Bart and Leclercq, Georges and Plum, Jean and Taghon, Tom},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {B-CELL,PROGENITOR CELLS,THYMUS MICROENVIRONMENT,BETA/GAMMA-DELTA,FATE,C-MYC,GENE-EXPRESSION,IN-VITRO,ANKYRIN-REPEAT PROTEIN,SIGNALING PATHWAY},
  language     = {eng},
  number       = {13},
  pages        = {2988--2998},
  title        = {An early decrease in Notch activation is required for human TCR-\ensuremath{\alpha}\ensuremath{\beta} lineage differentiation at the expense of TCR-\ensuremath{\gamma}\ensuremath{\delta} T cells},
  url          = {http://dx.doi.org/10.1182/blood-2008-06-164871},
  volume       = {113},
  year         = {2009},
}

Chicago
Van de Walle, Inge, Greet De Smet, Magda De Smedt, Bart Vandekerckhove, Georges Leclercq, Jean Plum, and Tom Taghon. 2009. “An Early Decrease in Notch Activation Is Required for Human TCR-αβ Lineage Differentiation at the Expense of TCR-γδ T Cells.” Blood 113 (13): 2988–2998.
APA
Van de Walle, I., De Smet, G., De Smedt, M., Vandekerckhove, B., Leclercq, G., Plum, J., & Taghon, T. (2009). An early decrease in Notch activation is required for human TCR-αβ lineage differentiation at the expense of TCR-γδ T cells. BLOOD, 113(13), 2988–2998.
Vancouver
1.
Van de Walle I, De Smet G, De Smedt M, Vandekerckhove B, Leclercq G, Plum J, et al. An early decrease in Notch activation is required for human TCR-αβ lineage differentiation at the expense of TCR-γδ T cells. BLOOD. 2009;113(13):2988–98.
MLA
Van de Walle, Inge, Greet De Smet, Magda De Smedt, et al. “An Early Decrease in Notch Activation Is Required for Human TCR-αβ Lineage Differentiation at the Expense of TCR-γδ T Cells.” BLOOD 113.13 (2009): 2988–2998. Print.