Metabolic switches of T-cell activation and apoptosis.
The signaling networks that mediate activation, proliferation, or programmed cell death of T lymphocytes are dependent on complex redox and metabolic pathways. T lymphocytes are primarily activated through the T-cell receptor and co-stimulatory molecules. Although activation results in lymphokine production, proliferation, and clonal expansion, it also increases susceptibility to apoptosis upon crosslinking of cell-surface death receptors or exposure to toxic metabolites. Activation signals are transmitted by receptor-associated protein tyrosine kinases and phosphatases through calcium mobilization to a secondary cascade of kinases, which in turn activate transcription factors initiating cell proliferation and cytokine production. Initiation and activity of cell death-mediating proteases are redox-sensitive and dependent on energy provided by ATP. Mitochondria play crucial roles in providing ATP for T-cell activation through the electron transport chain and oxidative phosphorylation. The mitochondrial transmembrane potential (DeltaPsi(m)) plays a decisive role not only by driving ATP synthesis, but also by controlling reactive oxygen species production and release of cell death-inducing factors. DeltaPsi(m) and reactive oxygen species levels are regulated by the supply of reducing equivalents, glutathione and thioredoxin, as well as NADPH generated in the pentose phosphate pathway. This article identifies redox and metabolic checkpoints controlling activation and survival of T lymphocytes.
Perl
Andras
A
Departments of Medicine, Microbiology and Immunology, and Pathology, State University of New York Upstate Medical University, College of Medicine, 750 East Adams Street, Syracuse, NY 13210, USA. perla@upstate.edu
Gergely
Peter
P
Puskas
Ferenc
F
Banki
Katalin
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001205:Ascorbic Acid / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*
D015703:Antigens, CD; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D000255:Adenosine Triphosphate; D005947:Glucose; D001205:Ascorbic Acid