Journal
BLOOD
Volume 113, Issue 14, Pages 3254-3263Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-07-168906
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Funding
- Odysseus program of the Fund for Scientific Research Flanders (FWO)
- Flemish Institute for the Advancement of Scientific-Technological Research in the Industry (IWT)
- Concerted Research Action of Ghent University (GOA)
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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. (Blood. 2009; 113:3254-3263)
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