02747nas a2200397 4500000000100000008004100001260001600042653002700058653001600085653001800101653002500119653003700144653001900181653001100200653001900211653002200230653003900252653003900291653003800330653001600368653002100384653002000405653002800425653003100453653002400484653001700508100001500525700001600540700002200556700001600578245008600594300001300680490000800693520163400701022001402335 2002 d c2002 May 3110aAntibodies, Monoclonal10aCD3 Complex10aCell Division10aCoculture Techniques10aDose-Response Relationship, Drug10aFlow Cytometry10aHumans10aImmunoblotting10aMembrane Proteins10aMitogen-Activated Protein Kinase 110aMitogen-Activated Protein Kinase 310aMitogen-Activated Protein Kinases10aNeutrophils10aOxidative Stress10aPhosphorylation10aReactive Oxygen Species10aReceptors, Antigen, T-Cell10aSignal Transduction10aTime Factors1 aCemerski S1 aCantagrel A1 aVan Meerwijk JP M1 aRomagnoli P00aReactive oxygen species differentially affect T cell receptor-signaling pathways. a19585-930 v2773 a
Oxidative stress plays an important role in the induction of T lymphocyte hyporesponsiveness observed in several human pathologies including cancer, rheumatoid arthritis, leprosy, and AIDS. To investigate the molecular basis of oxidative stress-induced T cell hyporesponsiveness, we have developed an in vitro system in which T lymphocytes are rendered hyporesponsive by co-culture with oxygen radical-producing activated neutrophils. We have observed a direct correlation between the level of T cell hyporesponsiveness induced and the concentration of reactive oxygen species produced. Moreover, induction of T cell hyporesponsiveness is blocked by addition of N-acetyl cysteine, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, and catalase, confirming the critical role of oxidative stress in this system. The pattern of tyrosine-phosphorylated proteins was profoundly altered in hyporesponsive as compared with normal T cells. In hyporesponsive T cells, T cell receptor (TCR) ligation no longer induced phospholipase C-gamma1 activation and caused reduced Ca(2+) flux. In contrast, despite increased levels of ERK1/2 phosphorylation, TCR-dependent activation of mitogen-activated protein kinase ERK1/2 was unaltered in hyporesponsive T lymphocytes. A late TCR-signaling event such as caspase 3 activation was as well unaffected in hyporesponsive T lymphocytes. Our data indicate that TCR-signaling pathways are differentially affected by physiological levels of oxidative stress and would suggest that although "hyporesponsive" T cells have lost certain effector functions, they may have maintained or gained others.
a0021-9258