Abstract
Notch signals are necessary for the functional outcomes of T cell receptor β-selection, including differentiation, proliferation and rescue from apoptosis. The mechanism underlying this requirement for T cell development is unknown. Here we show that Notch receptor and Delta-like 1 ligand interactions promoted the survival of CD4−CD8− pre–T cells through the maintenance of cell size, glucose uptake and metabolism. Furthermore, the trophic effects of Notch signaling were mediated by the pathway of phosphatidylinositol-3-OH kinase and the kinase Akt, such that expression of active Atk overcame the requirement for Notch in β-selection. Collectively, our results demonstrate involvement of Notch receptor–ligand interactions in the regulation of cellular metabolism, thus enabling the autonomous signaling capacity of the pre–T cell receptor complex.
*Note: In the version of this article initially published online, in the fourth sentence of the abstract, the term "Atk" was a misspelling; this should be "Akt." In the fourth sentence of the second paragraph of the introduction, the name of the second kinase mentioned, "PI(3)K-dependent kinase 1," was incorrect; this should read "phosphoinositide-dependent kinase 1." These errors have been corrected for the HTML and print versions of the article.
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Change history
14 August 2005
appended aop PDF with corrigendum (will be corrected for print issue), and placed footnote in XML at abstract
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Acknowledgements
We thank D.A. Vignali for the MIY retroviral vector; J. Maryanski for the MIG-TCRβ construct; W. Pear for the MigR retroviral vector; and G. Knowles for assistance in cell sorting. Supported by the Canadian Institutes of Health Research (Doctoral Research Award to M.C., and grant MOP 42387) and a Canada Research Chair in Developmental Immunology (J.C.Z.-P.).
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Supplementary information
Supplementary Fig. 1
The majority of Rag2−/− DN3 cells in OP9-DL1 and OP9-control cultures are non-cycling. (PDF 3241 kb)
Supplementary Fig. 2
Bcl-2 expression partially rescues the decline in cellularity following withdrawal of Notch-Delta-like-1 interaction. (PDF 1094 kb)
Supplementary Fig. 3
PI3K signals are indispensable for Notch-mediated trophic effects. (PDF 2995 kb)
Supplementary Table 1
Gene-specific primers used in RT-PCR analysis. (PDF 45 kb)
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Ciofani, M., Zúñiga-Pflücker, J. Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellular metabolism. Nat Immunol 6, 881–888 (2005). https://doi.org/10.1038/ni1234
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DOI: https://doi.org/10.1038/ni1234
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