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Notch signaling is required for proliferation but not for differentiation at a well-defined β-selection checkpoint during human T-cell development

Tom Taghon UGent, Inge Van de Walle UGent, Greet De Smet UGent, Magda De Smedt UGent, Georges Leclercq UGent, Bart Vandekerckhove UGent and Jean Plum UGent (2009) BLOOD. 113(14). p.3254-3263
abstract
Notch signaling is absolutely required for beta-selection during mouse T-cell development, both for differentiation and proliferation. In this report, we investigated whether Notch has an equally important role during human T-cell development. We show that human CD34(+) thymocytes can differentiate into CD4(+)CD8 beta(+) double positive (DP) thymocytes in the absence of Notch signaling. While these DP cells phenotypically resemble human beta-selected cells, they lack a T-cell receptor (TCR)-beta chain. Therefore, we characterized the beta-selection checkpoint in human T-cell development, using CD28 as a differential marker at the immature single positive CD4(+)CD3(-)CD8 alpha(-) stage. Through intracellular TCR-beta staining and gene expression analysis, we show that CD4(+)CD3(-) CD8 alpha(-)CD28(+) thymocytes have passed the beta-selection checkpoint, in contrast to CD4(+)CD3(-)CD8 alpha(-)CD28(-) cells. These CD4(+)CD3(-)CD8 alpha(-)CD28(+) thymocytes can efficiently differentiate into CD3(+)TCR alpha beta(+) human T cells in the absence of Notch signaling. Importantly, preselection CD4(+)CD3(-)CD8 alpha(-)CD28(-) thymocytes can also differentiate into CD3(+)TCR alpha beta(+) human T cells without Notch activation when provided with a rearranged TCR-beta chain. Proliferation of human thymocytes, however, is clearly Notch-dependent. Thus, we have characterized the beta-selection checkpoint during human T-cell development and show that human thymocytes require Notch signaling for proliferation but not for differentiation at this stage of development.
Please use this url to cite or link to this publication:
author
organization
alternative title
Notch signaling is required for proliferation but not for differentiation at a well-defined beta-selection checkpoint during human T-cell development
year
type
journalArticle (original)
publication status
published
subject
keyword
THYMUS MICROENVIRONMENT, LINEAGE COMMITMENT, PROGENITOR CELLS, FATE, EXPRESSION, DELTA, RECEPTOR, PRE-TCR, ACUTE LYMPHOBLASTIC-LEUKEMIA, ALPHA-BETA
journal title
BLOOD
Blood
volume
113
issue
14
pages
3254 - 3263
Web of Science type
Article
Web of Science id
000264848900019
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-2008-07-168906
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
604298
handle
http://hdl.handle.net/1854/LU-604298
date created
2009-04-30 09:29:56
date last changed
2011-04-14 10:28:06
@article{604298,
  abstract     = {Notch signaling is absolutely required for beta-selection during mouse T-cell development, both for differentiation and proliferation. In this report, we investigated whether Notch has an equally important role during human T-cell development. We show that human CD34(+) thymocytes can differentiate into CD4(+)CD8 beta(+) double positive (DP) thymocytes in the absence of Notch signaling. While these DP cells phenotypically resemble human beta-selected cells, they lack a T-cell receptor (TCR)-beta chain. Therefore, we characterized the beta-selection checkpoint in human T-cell development, using CD28 as a differential marker at the immature single positive CD4(+)CD3(-)CD8 alpha(-) stage. Through intracellular TCR-beta staining and gene expression analysis, we show that CD4(+)CD3(-) CD8 alpha(-)CD28(+) thymocytes have passed the beta-selection checkpoint, in contrast to CD4(+)CD3(-)CD8 alpha(-)CD28(-) cells. These CD4(+)CD3(-)CD8 alpha(-)CD28(+) thymocytes can efficiently differentiate into CD3(+)TCR alpha beta(+) human T cells in the absence of Notch signaling. Importantly, preselection CD4(+)CD3(-)CD8 alpha(-)CD28(-) thymocytes can also differentiate into CD3(+)TCR alpha beta(+) human T cells without Notch activation when provided with a rearranged TCR-beta chain. Proliferation of human thymocytes, however, is clearly Notch-dependent. Thus, we have characterized the beta-selection checkpoint during human T-cell development and show that human thymocytes require Notch signaling for proliferation but not for differentiation at this stage of development.},
  author       = {Taghon, Tom and Van de Walle, Inge and De Smet, Greet and De Smedt, Magda and Leclercq, Georges and Vandekerckhove, Bart and Plum, Jean},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {THYMUS MICROENVIRONMENT,LINEAGE COMMITMENT,PROGENITOR CELLS,FATE,EXPRESSION,DELTA,RECEPTOR,PRE-TCR,ACUTE LYMPHOBLASTIC-LEUKEMIA,ALPHA-BETA},
  language     = {eng},
  number       = {14},
  pages        = {3254--3263},
  title        = {Notch signaling is required for proliferation but not for differentiation at a well-defined \ensuremath{\beta}-selection checkpoint during human T-cell development},
  url          = {http://dx.doi.org/10.1182/blood-2008-07-168906},
  volume       = {113},
  year         = {2009},
}

Chicago
Taghon, Tom, Inge Van de Walle, Greet De Smet, Magda De Smedt, Georges Leclercq, Bart Vandekerckhove, and Jean Plum. 2009. “Notch Signaling Is Required for Proliferation but Not for Differentiation at a Well-defined Β-selection Checkpoint During Human T-cell Development.” Blood 113 (14): 3254–3263.
APA
Taghon, T., Van de Walle, I., De Smet, G., De Smedt, M., Leclercq, G., Vandekerckhove, B., & Plum, J. (2009). Notch signaling is required for proliferation but not for differentiation at a well-defined β-selection checkpoint during human T-cell development. BLOOD, 113(14), 3254–3263.
Vancouver
1.
Taghon T, Van de Walle I, De Smet G, De Smedt M, Leclercq G, Vandekerckhove B, et al. Notch signaling is required for proliferation but not for differentiation at a well-defined β-selection checkpoint during human T-cell development. BLOOD. 2009;113(14):3254–63.
MLA
Taghon, Tom, Inge Van de Walle, Greet De Smet, et al. “Notch Signaling Is Required for Proliferation but Not for Differentiation at a Well-defined Β-selection Checkpoint During Human T-cell Development.” BLOOD 113.14 (2009): 3254–3263. Print.