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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
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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.
Keywords
THYMUS MICROENVIRONMENT, LINEAGE COMMITMENT, PROGENITOR CELLS, FATE, EXPRESSION, DELTA, RECEPTOR, PRE-TCR, ACUTE LYMPHOBLASTIC-LEUKEMIA, ALPHA-BETA

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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 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.
@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},
  keywords     = {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 β-selection checkpoint during human T-cell development},
  url          = {http://dx.doi.org/10.1182/blood-2008-07-168906},
  volume       = {113},
  year         = {2009},
}

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