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Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellular metabolism

Nature Immunology volume 6, pages 881–888 (2005)Cite this article

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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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Figure 1: Requirement for Notch receptor and Delta-like 1 ligand interaction for TCR β-selection and pre–T cell survival.
Figure 2: Rag2−/− DN3 cells undergo apoptosis after withdrawal of Notch receptor–ligand interaction.
Figure 3: Rag2−/− DN3 cells undergo death and atrophy despite continued Bcl-2 expression.
Figure 4: Notch signals maintain glucose metabolism in pre–T cells.
Figure 5: Decreased Akt phosphorylation in the absence of Notch–Delta-like 1 ligand interactions.
Figure 6: Active Akt can restore the viability, cellular atrophy and decreased glycolytic rate of DN3 cells in the absence of Notch signaling.
Figure 7: Expression of active Akt restores the DN-to-DP transition in the absence of Notch–Delta-like 1 interaction.

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  • 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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Authors and Affiliations

  1. Department of Immunology, University of Toronto, Sunnybrook and Women's Research Institute, Toronto, M4N 3M5, Ontario, Canada

    Maria Ciofani & Juan Carlos Zúñiga-Pflücker

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  1. Maria Ciofani
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Correspondence to Juan Carlos Zúñiga-Pflücker.

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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)

Supplementary Methods (PDF 42 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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