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Redox regulation of signal transduction: tyrosine phosphorylation and calcium influx
F J Staal1, M T Anderson, G E Staal
1Department of Genetics, Stanford University School of Medicine, CA 94305.
Abstract:
Studies presented here show that altering the intracellular redox balance by decreasing glutathione levels profoundly affects early signal transduction events in human T cells. In a T-cell receptor (TCR) signaling model, short-term pretreatment with buthionine sulfoximine, which specifically decreases intracellular glutathione, essentially abrogates the stimulation of calcium influx by anti-CD3 antibodies without significantly impairing other aspects of TCR-initiated signal transduction, such as overall levels of TCR-stimulated tyrosine phosphorylation. In an inflammatory-cytokine signaling model, the failure of tumor necrosis factor alpha to stimulate more than minimal tyrosine phosphorylation in lymphocytes is overcome by buthionine sulfoximine pretreatment--i.e., tumor necrosis factor alpha stimulates extensive tyrosine phosphorylation in glutathione-depleted lymphocytes. These redox-dependent changes in T-cell responsiveness suggest that the glutathione deficiency that we and others have demonstrated in human immunodeficiency virus-infected individuals may contribute significantly to the immunodeficiency and the increased inflammatory reactions in these individuals.
Insights
Decreasing glutathione levels in T cells disrupts calcium signaling and enhances inflammatory responses. This redox imbalance may explain immune deficiency in HIV patients.
Area of Science:
- Immunology
- Cellular Signaling
- Redox Biology
Background:
- Glutathione is a key intracellular antioxidant crucial for maintaining cellular redox balance.
- Alterations in glutathione levels are observed in various disease states, including HIV infection.
- T cell signaling pathways are critical for immune responses and can be influenced by cellular redox status.
Purpose of the Study:
- To investigate the impact of reduced glutathione levels on T cell signaling pathways.
- To determine the role of intracellular redox balance in T cell receptor (TCR) and inflammatory cytokine signaling.
- To explore the potential contribution of glutathione deficiency to immunodeficiency in HIV-infected individuals.
Main Methods:
- Utilized buthionine sulfoximine to specifically decrease intracellular glutathione levels in human T cells.
- Examined T cell signaling in response to anti-CD3 antibodies (TCR signaling model).
- Assessed T cell responses to tumor necrosis factor alpha (inflammatory cytokine signaling model).
- Measured calcium influx and tyrosine phosphorylation as key signaling events.
Main Results:
- Short-term glutathione depletion abrogated anti-CD3 antibody-stimulated calcium influx in T cells.
- Overall levels of TCR-stimulated tyrosine phosphorylation were not significantly impaired by glutathione depletion.
- Glutathione depletion overcame the failure of tumor necrosis factor alpha to stimulate tyrosine phosphorylation in lymphocytes.
- Tumor necrosis factor alpha induced extensive tyrosine phosphorylation in glutathione-depleted lymphocytes.
Conclusions:
- Intracellular glutathione levels profoundly affect early signal transduction events in human T cells.
- Redox-dependent changes in T cell responsiveness highlight the importance of glutathione in immune function.
- Glutathione deficiency in HIV-infected individuals may significantly contribute to their immunodeficiency and inflammatory reactions.