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Papers In Press, published online ahead of print March 26, 2002
Tolerance and autoimmunity section, INSERM, Toulouse 31024
Corresponding Author: Paola.Romagnoli{at}toulouse.inserm.fr
Oxidative stress plays and 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 (ROS) produced. Moreover, induction of T cell hyporesponsiveness is blocked by addition of N-acetyl cysteine(NAC),Mn(IIItetrakis(4-benzoic acid)porphyrin chloride (MnTBAP)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 to normal T cells. In hyporesponsive T cells TCR-ligation did no longer induce PLC-g1 activation and caused reduced Ca2+ flux. In contrast, despite increased level of ERK1/2 phosphorylation, TCR-dependent activation of MAP-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 while "hyporesponsive" T cells have lost certain effector functions they may have maintained or gained others.
J. Biol. Chem, 10.1074/jbc.M111451200
Submitted on November 30, 2001
Revised on March 26, 2002
Accepted on March 26, 2002
Reactive oxygen species differentially affect T cell receptor signaling pathways
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