Gamma-glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis.
The ectoenzyme gamma-glutamyl transpeptidase (GGT) is absent on resting naive peripheral blood T cells, highly expressed upon stimulation and intermediate on resting memory T cells. In other tissues, GGT is essential for the recapture of the antioxidant glutathione (GSH). T cells with different levels of GGT activity were examined for their ability to withstand oxidative stress. To create a model system that reflected the level of GGT seen on naive and memory T cells, Jurkat T cells were cloned by limiting dilution and their GGT expression analyzed. Jurkat expressing GGT at levels comparable to resting memory T cells have levels of intracellular reactive oxygen species (ROS) that are only 65% that seen in Jurkat that have low levels of GGT (similar to naive T cells). Treatment of the cells with H(2)O(2) increases ROS in both cells, although the level seen in the GGT(high) Jurkat is less than half that in the GGT(low) variant. Despite protection from oxidative stress, the GGT(high) Jurkat were found to be 2- to 3-fold more sensitive to Fas-induced apoptosis. The redox-regulated NF-kappaB pathway is activated in GGT(low) cells, resulting in higher levels of cIAP-1/2 proteins that limit caspase activity. The GGT(low) cells were found to have higher levels of NF-kappaB in the nucleus as well as lower levels of IkappaB-alpha. The GGT(low) cells also express higher levels of the caspase inhibitors cIAP-1/2 and have lower levels of caspase activity. These findings suggest that GGT expression regulates ROS in T lymphocytes and modulates Fas-induced killing by altering NF-kappaB activity.
Carlisle
Margaret L
ML
Simmons Arthritis Research Center, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
King
Miranda R
MR
Karp
David R
DR
D017209:Apoptosis / Q000187:drug effects; D020169:Caspases; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019014:fas Receptor; D005723:gamma-Glutamyltransferase; D020169:Caspases; D005978:Glutathione