Reactive oxygen species differentially affect T cell receptor-signaling pathways.
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.
Cemerski
Saso
S
Tolerance and Autoimmunity section, INSERM U563, IFR 30 Institute Claude de Preval, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France.
Cantagrel
Alain
A
Van Meerwijk
Joost P M
JP
Romagnoli
Paola
P
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis; D002455:Cell Division; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases