γ-Glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis

The ectoenzyme γ-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 H₂O₂ 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-κB 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-κB in the nucleus as well as lower levels of IκB-α. 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-κB activity.