Metabolic control of T cell activation and death in SLE.
Systemic lupus erythematosus (SLE) is characterized by abnormal T cell activation and death, processes which are crucially dependent on the controlled production of reactive oxygen intermediates (ROI) and of ATP in mitochondria. The mitochondrial transmembrane potential (Deltapsi(m)) has conclusively emerged as a critical checkpoint of ATP synthesis and cell death. Lupus T cells exhibit persistent elevation of Deltapsi(m) or mitochondrial hyperpolarization (MHP) as well as depletion of ATP and glutathione which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. NO-induced mitochondrial biogenesis in normal T cells accelerates the rapid phase and reduces the plateau of Ca(2+) influx upon CD3/CD28 co-stimulation, thus mimicking the Ca(2+) signaling profile of lupus T cells. Treatment of SLE patients with rapamycin improves disease activity, normalizes CD3/CD28-induced Ca(2+) fluxing but fails to affect MHP, suggesting that altered Ca(2+) fluxing is downstream or independent of mitochondrial dysfunction. Understanding the molecular basis and consequences of MHP is essential for controlling T cell activation and death signaling in SLE.
Fernandez
David
D
Division of Rheumatology, Department of Medicine, State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York 13210, USA.
Perl
Andras
A
D000818:Animals; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D016923:Cell Death / Q000235:genetics / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008564:Membrane Potentials / Q000276:immunology; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D017252:CD3 Complex; D020123:Sirolimus