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

Nat Immunol. 2005 Sep;6(9):881-8. doi: 10.1038/ni1234. Epub 2005 Jul 31.

Abstract

Notch signals are necessary for the functional outcomes of T cell receptor beta-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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation / immunology
  • Cell Line
  • Cell Size
  • Cell Survival
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Glucose / metabolism
  • Glycolysis
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Notch1 protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Rag2 protein, mouse
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Cell Surface
  • Transcription Factors
  • V(D)J recombination activating protein 2
  • delta protein
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose