Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism.
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.
Ciofani
Maria
M
Department of Immunology, University of Toronto, Sunnybrook and Women's Research Institute, Toronto, Ontario M4N 3M5, Canada.
Zúñiga-Pflücker
Juan Carlos
JC
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D048429:Cell Size; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005947:Glucose; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C497762:Notch1 protein, mouse; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C064045:delta protein