REDOX REGULATION OF SIGNAL-TRANSDUCTION - TYROSINE PHOSPHORYLATION AND CALCIUM INFLUX

Studies presented here show that altering the intracellular redox bala nce by decreasing glutathione levels profoundly affects early signal t ransduction events in human T cells. In a T-cell receptor (TCR) signal ing model, short term pretreatment with buthionine sulfoximine, which specifically decreases intracellular glutathione, essentially abrogate s the stimulation of calcium influx by anti-CD3 antibodies without sig nificantly impairing other aspects of TCR-initiated signal transductio n, such as overall levels of TCR-stimulated tyrosine phosphorylation. In an inflammatory-cytokine signaling model, the failure of tumor necr osis factor alpha to stimulate more than minimal tyrosine phosphorylat ion in lymphocytes is overcome by buthionine sulfoximine pretreatment- i,e., tumor necrosis factor alpha stimulates extensive tyrosine phosph orylation in glutathione-depleted lymphocytes. These redox-dependent c hanges in T-cell responsiveness suggest that the glutathione deficienc y that we and others have demonstrated in human immunodeficiency virus -infected individuals may contribute significantly to the immunodefici ency and the increased inflammatory reactions in these individuals.