In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability.
Without receptor stimulation, cells from multicellular organisms die by apoptosis. Here we show that lymphocytes deprived of receptor stimulation undergo progressive atrophy before commitment to apoptosis. Following loss of receptor engagement, lymphocytes rapidly downregulated the glucose transporter, glut1. This was accompanied by reduction in mitochondrial potential and cellular ATP, suggesting that atrophy resulted from depletion of glucose-derived metabolic substrates. Expression of the antiapoptotic protein, Bcl-X(L), prevented death but not atrophy following either growth factor or glucose withdrawal. In Bcl-X(L) transgenic animals, size and metabolic activity of naive T cells were regulated through the TCR and correlated with TCR-dependent glut1 expression. These data suggest that ligands for cell-specific receptors promote cell survival by regulating nutrient uptake and utilization.
Rathmell
J C
JC
Department of Cancer Biology and Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia 19104, USA.
Vander Heiden
M G
MG
Harris
M H
MH
Frauwirth
K A
KA
Thompson
C B
CB
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001284:Atrophy; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000493:pharmacokinetics*; D051272:Glucose Transporter Type 1; D006133:Growth Substances / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics; D007377:Interleukin-3 / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D051020:bcl-X Protein
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; C494812:Bcl2l1 protein, mouse; D051272:Glucose Transporter Type 1; D006133:Growth Substances; D018398:Homeodomain Proteins; D007377:Interleukin-3; D008024:Ligands; D009004:Monosaccharide Transport Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; C495678:Slc2a1 protein, mouse; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; D051020:bcl-X Protein; C064658:RAG-1 protein; D000255:Adenosine Triphosphate; D005947:Glucose