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J. Biol. Chem., Vol. 277, Issue 22, 19585-19593, May 31, 2002

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Reactive Oxygen Species Differentially Affect T Cell Receptor-signaling Pathways^*

Saso Cemerski, Alain Cantagrel^§, Joost P. M. van Meerwijk^¶, and Paola Romagnoli^**

From the  Tolerance and Autoimmunity section, INSERM U563, IFR 30 Institute Claude de Preval, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France, ^¶ Faculty of Life Sciences (UFR-SVT), University Toulouse III, 31062 Toulouse Cedex 4, France, ^§ Department of Rheumatology, Rangueil Hospital, 31403 Toulouse Cedex 4, France, and  Institut Universitaire de France, 75005 Paris, France

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-1 activation and caused reduced Ca²⁺ 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.

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